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Current Vascular Pharmacology, 2005, 3, 169-180 169
1570-1611/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
The Emerging Roles of Leptin and Ghrelin in Cardiovascular Physiology
and Pathophysiology
Vijay Sharma* and John H. McNeill
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia,
2146 East Mall, Vancouver, Canada
Abstract: Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite.
More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin in-
creases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin pro-
duces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has
a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothe-
lium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may
contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-
inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be
anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet ag-
gregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their patho-
physiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.
Keywords: Leptin, ghrelin, obesity, metabolic syndrome, hypertension, heart failure, atherosclerosis, thrombosis.
INTRODUCTION
The History of Leptin
In 1950, Ingalls et al. identified an autosomal recessive
genetic defect in inbred obese [ob/ob] mice which produces a
phenotype of severe obesity, type 2 diabetes and infertility
[1]. In the 1970’s, Coleman undertook a series of parabiosis
experiments in which the circulation of the ob/ob mice was
linked to that of normal mice with the same genetic back-
ground [2, 3]. This suggested that the ob/ob mice lacked a
blood borne satiety factor. In 1991, it was confirmed that the
ob/ob mouse phenotype was produced by a mutation in the
ob gene [4]. Friedman’s group reported the positional clon-
ing of the mouse ob gene and its human homologue [5], and
its product was named leptin, from the greek word λεπτοσ
(leptos) which means thin.
Leptin is synthesised and secreted mainly by white adi-
pocytes in response to an increase in either their size or
number [6]. However, it is now known that leptin synthesis
and secretion is subject to regulation by many additional
factors including glucocorticoids, insulin, inflammatory me-
diators and sympathetic nervous activity [7]. When leptin
reaches the central nervous system it reduces appetite and
increases the basal metabolic rate [5]. In the years since its
discovery, leptin has also been found to produce effects on a
wide range of peripheral systems including the male and
female reproductive organs, mammary gland, immune sys-
tem, gut, pancreas, kidney, lung and vasculature (see [8-10]
for review).
*Address correspondence to this author at the Division of Pharmacology
and Toxicology, Faculty of Pharmaceutical Sciences, 2146 East Mall, Uni-
versity of British Columbia, Vancouver, Tel: (604) 822 6159, Fax: (604)
822 8001, E-mail: vijaysha@interchange.ubc.ca.
The History of Ghrelin
In an effort to develop new treatments for patients with
growth hormone deficiency, the first growth hormone se-
cretagogues (GHS) were synthesised in the late 1970’s [11].
It became clear that these compounds were not acting on the
growth hormone receptor, and the GHS receptors (GHS-R)
were cloned in 1996 following a series of studies on MK-
0677, the most powerful GHS known [12]. In 1999, a group
of Japanese scientists discovered that exposure of GHS-R-
expressing cells to stomach extracts caused a marked in-
crease in calcium concentration, a known downstream effect
of GHS-R stimulation. They purified and characterised the
molecule responsible for this effect, and named it ghrelin,
from ghre-, the proto-Indo-European root of the word
‘grow’.
Although originally identified as the endogenous growth
hormone secretagogue, ghrelin has more important effects on
the regulation of food intake. It is an orexant, secreted in a
pulsatile fashion from the stomach [13], and is a counter-
regulatory hormone to leptin in the central control of appetite
(see [14] for review). Ghrelin also has a range of other cen-
tral and peripheral effects, including effects on gastric motil-
ity and acid secretion, pancreatic function, male reproductive
organs, lactotroph and corticotroph secretion, sleep and the
cardiovascular system (see [15] for review).
This review will focus on the role of leptin and ghrelin in
the pathophysiology of a variety of cardiovascular diseases
including obesity hypertension, atherosclerosis, heart failure
and thrombosis.
OBESITY HYPERTENSION
The incidence of obesity in industrialised countries has
reached epidemic proportions [16], and is associated with
170 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
increased cardiovascular morbidity and mortality [17]. Obe-
sity initiates a range of cardiovascular (hypertension, obe-
sity-related cardiomyopathy), metabolic (hyperinsulinemia,
hypertriglyceridemia, reduced high density lipoprotein lev-
els, type 2 diabetes) and renal abnormalities which are col-
lectively referred to as the metabolic syndrome [18]. The
mechanisms underlying the interrelationships between these
disorders are complex and have been the subject of intense
study in recent years.
There is a clear link between excess weight and the de-
velopment of insulin resistance and hypertension which has
been shown both experimentally [19-21] and clinically [22-
24]. Obesity is associated with abnormal renal function [25],
activation of the sympathetic nervous system [26] and en-
dothelial dysfunction [27], all of which lead to hypertension.
Leptin plays an important role in the development of obesity
[28, 29] and there is growing evidence that it may also medi-
ate some of the subsequent deleterious effects on the cardio-
vascular system.
Epidemiological studies have shown that leptin is posi-
tively correlated with blood pressure [30-32] and insulin
resistance [33, 34]. A tetranucleotide repeat polymorphism
in the leptin gene is more frequent in hypertensive subjects
[35, 36], and polymorphisms in the leptin receptor gene in-
crease the risk of hypertension in male subjects [36]. How-
ever, the relationship is not straightforward. The correlation
between leptin and hypertension is dependent on gender –
females have higher leptin levels but lower blood pressure
than do males [37] – and race [38-40]. Also, even though
visceral obesity is more closely associated with hypertension
than lower body obesity, it causes smaller increases in leptin
[41]. In contrast, ghrelin produces beneficial effects on the
vasculature [42], and is inversely correlated with hyperten-
sion, insulin resistance and Type 2 diabetes [43, 44]. Addi-
tionally, the Arg51Gln mutation in the ghrelin gene is a risk
factor for hypertension, impaired glucose tolerance and type
2 diabetes [45].
Peripheral Vascular Effects of Leptin and Ghrelin
When leptin is administered intravenously (IV) or intrac-
erebroventricularly (ICV), sympathetic nerve activity in-
creases in the kidneys, adrenals, brown adipose tissue (BAT)
and a number of vascular beds in a dose and time-dependent
manner [46, 47]. Despite this, acute administration of leptin
does not increase blood pressure [46, 47]. When large doses
of leptin are given directly into the cerebral ventricles, a
modest increase in blood pressure is observed [48].
It has been suggested that there is an acute depressor ef-
fect of leptin which counteracts the effects of increased sym-
pathetic activity on the vasculature and prevents an increase
in blood pressure [49]. The nature of this depressor effect is
controversial. Leptin receptors are present on endothelial
cells, and leptin has been shown to cause endothelium-
dependent vasodilation of rat aortic rings which is prevented
in the presence of a nitric oxide (NO) inhibitor [49, 50].
Leptin has also been shown to induce NO production by ac-
tivating the Akt-endothelial NO synthase (eNOS) pathway in
rat aortic rings [51], an effect which may be enhanced by
insulin [52]. A pressor effect of leptin is observed in anes-
thetised animals treated with a NO inhibitor, and a depressor
effect is observed in animals with pharmacologically in-
duced ganglionic blockade [53]. Leptin replacement in the
ob/ob mouse reverses endothelial dysfunction [54], and pre-
incubation of endothelial cells with leptin increases NO pro-
duction in this model [55]. These data suggest that leptin
produces peripheral vasodilation by stimulating endothe-
lium-derived NO.
Fig. (1). Summary of the effects of leptin and ghrelin in the central control of appetite and metabolism.
The Emerging Roles of Leptin and Ghrelin Current Vascular Pharmacology, 2005, Vol. 3, No. 2 171
In contrast with these data, leptin does not have any
vasodilator effects on mesenteric vessels in conscious Spra-
gue-Dawley rats [56], nor does it have any vasoconstrictor
effects on renal, mesenteric or hindquarters blood flow in
conscious Long-Evans rats treated with a NOS inhibitor
[57]. Further, β-adrenergic blockade does not change blood
flow in the presence of leptin. These results argue against the
hypothesis that leptin causes vasodilation by a NO-
dependent mechanism.
Leptin has been shown to increase blood flow in the hu-
man forearm [58] and cause vasodilation in human coronary
arteries in vivo [59]. Both effects were preserved in the pres-
ence of a NO inhibitor, suggesting that they were not medi-
ated by NO. Renal and hindlimb vasoconstriction produced
by direct stimulation of sympathetic nerves is not attenuated
by the administration of leptin [60]. It is therefore unclear
whether the ability of leptin to stimulate endothelial NO pro-
duction is of any significance in vivo as it has not been con-
sistently reported, and, if present, may be insufficient to
overcome the vasoconstriction produced by sympathetic
nerve activation.
There are several possible explanations for the contra-
dictory findings discussed above. The NO-effect may be
limited to the conduit vessels, or occur only at pharmacol-
ogical doses. The use of anesthesia may have influenced the
in vivo data; the studies which saw no alteration in blood
flow were done in awake animals [56]. It is also possible that
other vasodilator substances contribute to the leptin re-
sponse. The endothelium secretes prostacylin [PGI2] and an
unknown factor dubbed endothelium derived hyperpolariz-
ing factor [EDHF]. EDHF stimulates the calcium-sensitive
potassium channels on the smooth muscle cell, hyperpolar-
izing the cell and causing vasorelaxation. There is evidence
to suggest that the importance of the hyperpolarizing mecha-
nism may increase as the size of the vessel decreases [61]. It
has been shown that whilst NO is the major mediator of
leptin induced vasodilation in rat aorta, EDHF is the major
mediator of leptin induced vasodilation in the mesenteric
artery [49]. This raises the possibility that leptin may stimu-
late the production of both NO and EDHF, with the relative
importance of each varying depending on the vessel. It
would be interesting to determine whether leptin stimulated
EDHF production is able to compensate for the lack of NO
production when NOS is inhibited. EDHF is able to compen-
sate for the lack of NO in eNOS knockout mice [62]. Addi-
tionally, it has been shown that the release of EDHF is at-
tenuated by NO [63]. The role of EDHF in mediating leptin-
induced vasodilation is therefore worthy of further study.
Leptin has been shown to increase the formation of reac-
tive oxygen species [ROS] in cultured endothelial cells. It is
not clear which ROS are generated; hydrogen peroxide,
which is also a putative EDHF [64], and superoxide have
both been suggested [65]. ROS scavenge and inactivate NO,
thereby promoting vasoconstriction, and cause direct endo-
thelial and smooth muscle damage. Leptin has also been
Fig. (2). Summary of the central and peripheral actions of leptin in the modulation of blood pressure (CNS = central nervous system; α-MSH
= α-melanocyte stimulating hormone; CART = cocaine- and amphetamine-related transcript peptide; NPY = neuropeptide Y; CRF = corti-
cotrophin releasing factor; AG-II = angiotensin II; SNS = sympathetic nervous system; ET-1 = endothelin-1; ROS = reactive oxygen species;
NO = nitric oxide; EDHF = endothelium-derived hypepolarising factor; BAT = brown adipose tissue).
172 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
shown to stimulate the production of endothelin-1 (ET-1), a
potent vasoconstrictor mitogen secreted by the endothelium,
in human umbilical vein endothelial cells in vitro [66]. This
raises the possibility that leptin can act directly on the endo-
thelium to produce vasoconstrictor effects. The picture is
further complicated by the observation that leptin blocks the
vasoconstrictor actions of angiotensin II in the rat aorta [67].
Whereas short term administration of leptin has no pres-
sor effect, long term administration does cause an increase in
blood pressure in rodents. When leptin was infused for 12
days, reaching blood levels comparable to those found in
obesity, mean arterial blood pressure and heart rate gradually
increased [68]. Ectopic secretion of leptin from the liver,
which occurs in the transgenic skinny mouse model, also
increases blood pressure. This increase is prevented by com-
bined α- and β- adrenergic blockade, or by ganglionic block-
ade [69]. α- and β- adrenergic blockade also prevents the
increase in blood pressure caused by long term leptin infu-
sion, although other effects of leptin are preserved [70]. In-
creased sympathetic outflow is therefore essential for the
pressor effects of leptin. If a compensatory vasodilator
mechanism is activated by the acute administration of leptin,
it is clearly overcome by, or diminishes with, chronic ad-
ministration.
It is interesting to note that whereas leptin stimulates the
activity of the sympathetic nervous system, the sympathetic
nervous system in turn inhibits the secretion of leptin, pro-
viding a negative feedback loop (see [71] for review). It has
been suggested that a breakdown in this feedback may be a
risk factor for excess weight gain [72], thereby implicating it
as a possible early step in the development of obesity and its
complications.
Clinical data about the effects of leptin on the sympa-
thetic nervous system are sparse (see [73] for review). Leptin
has rarely been administered to human subjects, so the best
clinical evidence available is from correlation studies. Some
studies have shown a positive correlation between sympa-
thetic activation and leptin levels [74-77] whereas others
have not [78]. Most of our information about the sympathetic
effects of leptin comes from animal studies; what happens in
humans is still unclear.
In contrast to leptin, ghrelin has depressor actions when
administered IV to healthy men [42] or given intracerebrov-
entricularly to conscious rabbits [79]. The pressor effect oc-
curs without an increase in heart rate [42], and is associated
with renal sympathoinhibition [79]. Sub-depressor doses of
ghrelin augment the baroreceptor reflex, as evidenced by
heart rate and renal sympathetic nerve activity [79]. These
effects appear to be caused by ghrelin itself rather than
growth hormone, because they are not produced by growth
hormone alone [80] and, with regard to ghrelin’s central
orexigenic actions, are still seen in growth hormone deficient
spontaneous dwarf rats [81].
Ghrelin also produces direct effects on the peripheral
vascular system. GHS receptors are present in the heart and
blood vessels in both rats and humans [42, 82]. Ghrelin has
been shown to increase human forearm blood flow in a dose-
dependent manner [83]. In isolated human internal mammary
arteries preconstricted with ET-1, ghrelin produces vasodila-
tion by an endothelium-independent mechanism [84].
Chronic ghrelin treatment significantly increased circulating
insulin-like growth factor 1 [IGF-1] levels in rats, and this
was associated with a fall in peripheral resistance [85]. Since
IGF-1 produces vasodilation by stimulating NO synthesis
[86], it has been suggested that part of ghrelin’s vasodilatory
effect may be mediated by IGF-1 [87]. However, the depres-
sor effect of ghrelin is unlikely to be solely due to peripheral
vasodilation because it occurs without an increase in pulse
rate. Further studies are required to further investigate these
effects of ghrelin and how they interact with the effects of
leptin.
Renal Effects of Leptin
Abnormal kidney function in obesity hypertension mani-
fests as a hypertensive shift of pressure natriuresis, resulting
in increased tubular reabsorption of sodium [25, 88]. In-
creased activity of renal sympathetic nerves [89, 90], activa-
tion of the renin-angiotensin system [89, 91] and physical
compression of the kidneys [88] all appear to contribute to
this dysfunction.
There is controversy in the literature as to whether leptin
can have direct diuretic and natriuretic effects, which would
tend to lower blood pressure. Acute administration of phar-
macological doses of leptin increases diuresis and natriuresis
[92, 93]. However, chronic administration of leptin has no
effect [94]. It has been suggested that leptin induced sym-
pathoactivation of renal nerves causes an adverse shift in the
pressure-natriuresis curve [73], because leptin is only able to
produce natriuresis in spontaneously hypertensive rats if the
kidneys are denervated [95]. The acute natriuretic effect of
leptin is attenuated in obese and hypertensive rats [93, 96].
Increased tubular reabsorption of sodium could therefore be
the result of sympathetic nerve activation causing a shift in
the pressure-natriuresis curve, and downregulation of leptin
receptors [97].
Fig. (3). Overview of the effects of leptin and ghrelin left ven-
tricular dysfunction and cardiac cachexia during heart failure (+ =
worsens; - = improves).
The Emerging Roles of Leptin and Ghrelin Current Vascular Pharmacology, 2005, Vol. 3, No. 2 173
Interaction Between Leptin and the Renin-Angiotensin
System
It is now known that adipose tissue contains all the com-
ponents of the renin-angiotensin system [73]. Angiotensin II
increases leptin production in vitro and in vivo [98] and is
known to potentiate sympathetic nervous system activity
[99]. It has been suggested that leptin and angiotensin II may
act synergistically in hypertension [73]. Whilst this is a very
reasonable hypothesis, it is interesting to note that leptin
blocks the vasoconstrictor effects of angiotensin II in the
aorta [67]. This is in keeping with the general picture of
leptin as acting peripherally to produce vasodilation, and
centrally to increase sympathetic outflow and cause vasocon-
striction. The interactions between leptin and the angiotensin
system require further study.
Central Effects of Leptin and Ghrelin in Blood Pressure
Regulation
The central nervous system mechanisms of leptin-
dependent sympathoactivation and ghrelin-dependent sym-
pathoinhibition have been reviewed in detail previously [41,
73, 100, 101]. Briefly, leptin-dependent sympathoactivation
occurs via several pathways. Firstly, Leptin stimulates the
melanocortin system. Melanocortins are a family of peptides
which are cleaved from the common precursor, proopiome-
lanocortin [POMC]. Leptin acts on the melanocortin-4 [MC-
4] receptor, causing increased expression of the melanocortin
α-melanocyte stimulating hormone [α-MSH]. This effect is
inhibited by agouti-related protein [AGRP], the endogenous
antagonist of the MC-3 and MC-4 receptors [for review, see
[41, 73, 100, 101]]. However, the intracerebroventricular
administration of synthetic MC-3 and MC-4 antagonists does
not lower blood pressure in the presence of hyperleptinaemia
[69]. Also, agouti mice, which overexpress AGRP, are still
hypertensive despite antagonism of the MC-4 receptor by the
high levels of AGRP [69, 102]. The melanocortin system
may not contribute significantly to the development of hy-
pertension in these cases. Leptin also stimulates the expres-
sion of another melanocortin, corticotrophin releasing factor
(CRF), which increases sympathetic outflow to BAT, but is
not implicated in the control of blood pressure [103, 104].
The pathways linking leptin to sympathetic modulation of
the cardiovascular system and metabolism are therefore
separate. This idea is further reinforced by the observation
that leptin-dependent renal sympathoactivation is attenuated
by the baroreceptor reflex whereas BAT sympathoactivation
is not [105].
Secondly, leptin stimulates cocaine- and amphetamine-
related transcript peptide [CART]. CART was originally
identified in rat striatum as a peptide which is induced fol-
lowing acute administration of cocaine or amphetamine
[106]. Stimulation of CART neurons by leptin leads to acti-
vation of sympathetic neurons [107] and elevation of blood
pressure [108]. The relative importance of each of these
pathways, as well as possible other undiscovered pathways,
remains to be determined.
A third pathway which is important in the regulation of
blood pressure involves neuropeptide Y, a widely expressed
neuropeptide in both the central and peripheral nervous sys-
tems. The effects of neuropeptide Y on central cardiovascu-
lar regulation are inhibited by leptin [109]. However, there is
controversy in the literature as to what these effects are, with
some groups reporting a decrease [109, 110] and others an
increase [111] in sympathetic activity.
Finally, leptin has been shown to inhibit orexins, peptides
which have been shown to cause sympathoactivation and
pressor responses [112-117]. This contrasts with leptin’s
other mechanisms of action in that it is inhibiting a sym-
Fig. (4). Modulation of the pathophysiological mechanisms of atherosclerosis by leptin and ghrelin.
174 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
pathoexcitatory pathway rather than stimulating it. The pur-
pose of this action is unclear. However, as orexins also
stimulate food intake [118], an inhibitory effect of leptin on
orexins is logical from the perspective of central appetite
control.
The central mechanisms of ghrelin’s actions have been
less clearly characterised. There is data to suggest that ghre-
lin may decrease sympathetic activity and modulate the
baroreceptor reflex through actions at the medulla oblongata
and the hypothalamic nucleus [119, 120]. However, it is not
yet clear which pathways are involved. Further studies are
required to determine the location and detailed mechanisms
of ghrelin’s actions.
Leptin Resistance
Obesity is associated with hyperleptinemia, and yet obese
subjects continue to ingest excess calories. This has been
interpreted as evidence of leptin ‘resistance’. Resistance to
leptin’s effects is seen in some rodent models of obesity
[121]. As discussed by Hall et al. [41], leptin resistance
could occur by three mechanisms: first, receptor or postre-
ceptor signalling defects at the level of the hypothalamus;
second, impaired leptin transport across the blood brain bar-
rier; third, overriding of leptin-stimulated effects at the level
of the hypothalamus by other factors. If leptin resistance is
global, then one would expect to see a blunted response to all
leptin’s actions, which would argue against leptin as a link
between obesity and hypertension.
Recently, it has been suggested that selective leptin re-
sistance occurs, with metabolic actions being affected and
cardiovascular actions spared [122]. This has been shown to
happen in obese agouti mice [123, 124]. However, leptin
receptor downregulation may occur in the kidney [97], and
leptin resistance may also occur in the heart [125], so periph-
eral vascular effects may not all be spared from leptin resis-
tance. The effects of short or long term administration of
leptin in lean and obese humans are unknown, so it is not
clear whether selective leptin resistance occurs in humans.
This requires clarification as it makes interpretation of the
effects of hyperleptinemia in human obesity difficult.
HEART FAILURE
Heart failure is a major health problem associated with
high mortality, frequent hospitalisation and poor quality of
life. Heart failure currently affects 5 million Americans, with
500,000 new cases diagnosed every year [126]. Ghrelin has
been shown to have beneficial effects on the cardiovascular
system, and may prove to be a useful treatment in severe
heart failure. This has been reviewed in detail recently [87]
so only a brief overview is given here.
As discussed in previous sections, ghrelin lowers blood
pressure and increases cardiac output [42] by both central
and peripheral mechanisms. Additionally, ghrelin inhibits
apoptosis of endothelial cells and cardiomyocytes in vitro
[127], and prevents cardiovascular damage after ischaemia-
reperfusion [128]. The administration of ghrelin has been
shown to improve cardiac performance in rats with heart
failure [85]. As reviewed by Nagaya and Kangawa [87], this
improvement could be due to the direct effects of ghrelin
preventing apoptosis and causing vasodilation, as well as
indirect effects on muscle growth mediated by the growth
hormone/ IGF-1 axis. Ghrelin does not appear to have a di-
rect positive inotropic effect [85]. Interestingly, murine and
human cardiomyocytes have been shown to synthesise ghre-
lin, and it is suggested that this serves to protect cardiomyo-
cytes against apoptosis [129].
Patients with end-stage chronic heart failure frequently
develop cardiac cachexia, a catabolic state associated with
weight loss and muscle wasting [130-132]. Cardiac cachexia
is a strong independent risk factor for mortality in heart fail-
ure [132]. Ghrelin may be a useful treatment for cardiac
cachexia both due to its direct effects on promoting feeding
and adiposity, and indirect effects on muscle growth, again
mediated by the growth hormone/ IGF-1 axis (see [87] for
review). Whether these beneficial effects of ghrelin are also
seen in patients with heart failure remains to be determined.
Leptin may have pathophysiological significance in heart
failure via a range of mechanisms. Chronic heart failure
(CHF) is associated with high levels of leptin in humans
[133]. Additionally, leptin levels correlate with New York
Heart Association (NYHA) functional class, suggesting that
leptin levels may be of prognostic value in CHF [134]. It is
interesting to note that leptin is an independent predictor of
the ventilatory response to exercise in CHF patients with
chronic heart failure [135], implicating leptin as a link be-
tween the metabolic, respiratory and cardiovascular abnor-
malities of this disease state; leptin is believed to be a neuro-
hormonal regulator of the respiratory centres in the brain
[136], which could partly explain this association. Further, it
is possible that hyperleptinemia also contributes to the cata-
bolic state which leads to cardiac cachexia [133].
Obese patients are at increased risk of heart failure; this
‘obesity-related cardiomyopathy’ is characterised by ven-
tricular dilation secondary to hypervolemia, and myocyte
hypertrophy [73]. The mechanisms of myocyte hypertrophy
in this condition are unclear. Myocardial wall thickness is
associated with plasma leptin levels in hypertensive men
[137]. This correlation is independent of blood pressure or
body composition. It has been suggested that leptin alters the
proliferative properties of cardiomyocytes, but the experi-
mental data are conflicting. One study showed that leptin
stimulated increased cell surface area, protein synthesis, and
the expression of α-skeletal actin and myosin light chain-2 in
neonatal rat ventricular myocytes [138]. However, leptin
deficient mice exhibit echocardiographic and histological
cardiomyocyte hypertrophy which is reversed by leptin re-
placement [139], suggesting that defective leptin signalling
and leptin resistance causes cardiac hypertrophy. Whether
leptin causes or prevents cardiomyocyte hypertrophy re-
quires further study. One possible explanation for the dis-
crepancy in these results is the use of neonatal heart cells in
the first study; the response to leptin may vary between neo-
nates and adults.
Leptin has a negative inotropic effect on isolated cardio-
myocytes which is NO-dependent [140]. This effect is abro-
gated in cardiomyocytes from spontaneously hypertensive
rats, as is the increase in NO [125]. These cardiomyocytes
therefore develop leptin resistance too. Long term treatment
with leptin reduced the activity of adenylate cyclase in rat
The Emerging Roles of Leptin and Ghrelin Current Vascular Pharmacology, 2005, Vol. 3, No. 2 175
cardiac cells and altered the response to catecholamines
[141]; this intriguing initial observation points to a possible
role for leptin in the altered responses of the heart to sym-
pathetic stimulation, providing another mechanism by which
leptin might modulate inotropy in the heart.
ATHEROSCLEROSIS
Atherosclerosis occurs as a result of vascular injury
which triggers an inflammatory and fibroproliferative re-
sponse. The prospective West of Scotland Coronary Preven-
tion Study [WOSCOPS] showed that leptin causes a modest
independent increase in the relative risk of coronary artery
disease [142]. This epidemiologic association could be ex-
plained by leptin’s effects on inflammation, cell prolifera-
tion, calcification and thrombosis, as well as by its effects on
autonomic function discussed above.
Leptin stimulates osteoblastic differentiation and calcifi-
cation of endothelial cells in vitro [143]. Calcification of
coronary arteries is associated with increased atherosclerotic
plaque burden [144, 145], increased risk of myocardial in-
farction [146, 147], and increased risk of dissection follow-
ing angioplasty [148]. Neointimal formation is reduced by
90% in leptin receptor-deficient mice [149], suggesting that
leptin is required for regeneration of the endothelial intimal
layer following injury. It also implicates leptin in the mecha-
nism of arterial restenosis following angioplasty. Leptin also
increases proliferation and migration of smooth muscle cells
in vitro by activating phosphatidylinositol-3-kinase and mi-
togen activated protein kinases [150]. The migration of
smooth muscle cells into the intimal layer is a key feature of
atherosclerosis. These data point to a role for leptin in vas-
cular remodelling which may be of pathophysiological sig-
nificance in atherosclerosis. Leptin could play a role in
restenosis after angioplasty. Whether leptin increases the risk
of dissection following angioplasty through its effects on
calcification is unknown.
Leptin may also stimulate low grade vascular inflamma-
tion [151]. Leptin deficient mice and leptin receptor deficient
mice have impaired immune function which, in the case of
the leptin deficient mice, is improved by leptin replacement
[152]. Leptin activates neutrophils, increases phagocytosis
by monocytes/ macrophages, and enhances the secretion of
pro-inflammatory mediators including tumor necrosis factor
and interleukins 2 and 6 (see [153] for review), all of which
could be of pathophysiological significance in atherosclero-
sis. As discussed above, leptin also increases oxidative
stress, which, in addition to causing direct endothelial dam-
age, also increases the secretion of atherogenic lipoprotein
lipase from macrophages in vitro [154]. The role of leptin in
mediating the specific inflammatory processes of atheroscle-
rosis requires further study. Clinical data linking leptin to
these inflammatory processes is scarce. In young healthy
men, leptin is independently associated with C reactive pro-
tein, a known marker of atherosclerosis [155]. By contrast,
ghrelin has recently been shown to inhibit the production of
proinflammatory cytokines and mononuclear cell binding in
endothelial cells in vitro, as well as endotoxin-induced cyto-
kine production in vivo [156]. This anti-inflammatory action
suggests that ghrelin may be beneficial in atherosclerosis.
The significance of the effects of leptin and ghrelin on
inflammation could also be extended to obesity, as it is now
recognised that obesity is a state of chronic inflammation.
Obesity is associated with increased plasma concentrations
of TNF α [157], C-reactive protein [158], interleukin-6 [159]
and plasminogen activator inhibitor-1 [160]. As discussed in
other sections, all of these can be stimulated by or are posi-
tively associated with leptin. Additionally, now that a role
for ghrelin in modulating inflammation has been identified,
its effects on the chronic inflammation of obesity can be
studied.
Interestingly, it has recently been shown that an immobi-
lised form of ghrelin copurifies with high density lipoprotein
(HDL) in vitro [161]. The possibility of a link between ghre-
lin and HDL is intriguing, but further studies are required to
investigate the nature and significance of this link. Whether a
physiologically significant interaction occurs between ghre-
lin and HDL in vivo, and how such an interaction might in-
fluence their respective physiological effects, is not known.
It is also not known whether ghrelin interacts with other
moieties in the blood.
THROMBOSIS
Atherothrombosis is accelerated in obesity. In addition to
the metabolic disorders present in obesity, which undoubt-
edly contribute significantly to this acceleration, it is possi-
ble that altered hemostatic balance in these patients is also
important [162, 163]. It has recently been shown that there is
an association between atherosclerosis and venous throm-
boembolism even after adjustment for typical risk factors for
both conditions [164]. Taken together, these data suggest
that there may be circulating factors which increase the risk
of both conditions; leptin may be one of these factors. The
mechanisms by which leptin may influence hemostasis have
been reviewed in detail recently [165], and only a brief over-
view is given here.
Leptin has recently been shown to promote platelet ag-
gregation in vitro [166] and in vivo [167]. In leptin-deficient
and leptin receptor-deficient mice, thrombotic occlusion after
arterial injury was delayed [167]. Leptin administration cor-
rected this dysfunction in the leptin-deficient mice only. This
was confirmed in a subsequent study which also linked the
prolonged time to occlusive thrombosis to leptin-deficient
hemopoietic tissues [168]. The mechanism of this effect ap-
pears to be coactivation of platelets with adenosine diphos-
phate (ADP) (see [165] for review). It is not clear whether
this also occurs in human platelets. Increased human platelet
aggregation requires doses of 100-500 ng/ml of leptin [166],
levels which are seldom seen clinically [169]. It is therefore
unclear whether leptin can produce a prothrombotic state in
humans by its effects on platelet activation.
Two further potential prothrombotic effects of leptin
have emerged. Leptin causes a modest decrease in the anti-
coagulant protein thrombomodulin in cultured human um-
bilical vein cells [170]. Also, leptin is associated with in-
creased tissue plasminogen activator inhibitor-1 activity and
decreased plasminogen activator-1 activity in both men and
post-menopausal women [171], suggesting that leptin may
inhibit fibrinolysis. Impaired fibrinolysis is a common find-
ing in obesity [172-174]. A recent study has shown that
176 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
leptin is associated with impaired fibrinolysis in overweight
hypertensive humans [175].
Leptin levels are increased in obesity [169], pregnancy
[176] and during treatment with antipsychotic drugs [177],
all of which are clinical situations in which the risk of
thromboembolic events is known to be increased. Hyper-
leptinemia was shown to be correlated with increased plate-
let aggregation in patients on continuous ambulatory perito-
neal dialysis for chronic renal failure [178]; cardiovascular
events related to thrombosis are an important cause of mor-
bidity and mortality in these patients [178]. Hyperleptinemia
is a risk marker for first ever hemorrhagic strokes in humans
[179, 180]. Leptin levels were raised in men who subse-
quently developed myocardial infarction, but its contribution
to the risk of myocardial infarction was not significant [181].
To our knowledge, there is no clinical data about the asso-
ciation of leptin with the risk of idiopathic venous throm-
boembolism. It has also been suggested that leptin may be a
useful marker with which to study the association between
thrombosis risk and oral contraceptive/ hormone replacement
therapy use [182]. Taken together, these data indicate that
leptin may contribute to a pro-thrombotic state in a range of
conditions, and this could be explained by its effects on
platelet aggregation, coagulation and fibrinolysis. To our
knowledge, there are no reports of ghrelin influencing hemo-
stasis.
SUMMARY
Leptin and ghrelin produce a range of effects on the car-
diovascular system which are of pathophysiological impor-
tance in a range of cardiovascular diseases. For the most
part, ghrelin’s effects are beneficial and leptin’s effects,
deleterious. Leptin causes sympathoactivation and ghrelin,
sympathoinhibition. Leptin and ghrelin are both vasodilators,
but leptin’s action is endothelium-dependent whereas ghre-
lin’s action appears to be endothelium-independent. Ghrelin
improves left ventricular function in heart failure through its
vasodilator effect and by inhibition of apoptosis. Leptin may
contribute to the development of heart failure in obese sub-
jects and epidemiological studies link it to heart failure.
Ghrelin improves cardiac cachexia, whereas leptin may con-
tribute to the catabolic state that leads to it. Leptin is pro-
inflammatory, whereas ghrelin is anti-inflammatory. Leptin
also has proliferative and calcification-promoting effects on
the endothelium. Finally, leptin may produce a pro-
thrombotic state through stimulation of platelet aggregation,
inhibition of coagulation and inhibition of fibrinolysis.
Ghrelin is not known to influence hemostasis. Further ex-
amination of the roles of these peptide hormones in cardio-
vascular pathology could lead to the identification of new
therapeutic strategies for the treatment of these diseases.
REFERENCES
[1] Ingalls AM, Dickie MM, Snell GD: Obese, a new mutation in the
house mouse. J Hered 41: 317-318, 1950
[2] Coleman DL: Effects of parabiosis of obese with diabetes and
normal mice. Diabetologia 9: 294-298, 1973
[3] Coleman DL: Obese and diabetes: two mutant genes causing
diabetes-obesity syndromes in mice. Diabetologia 14: 141-148,
1978
[4] Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N: Molecu-
lar mapping of the mouse ob mutation. Genomics 11: 1054-1062,
1991
[5] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman
JM: Positional cloning of the mouse obese gene and its human
homologue. Nature 372: 425-432, 1994
[6] Klein S, Coppack SW, Mohamed-Ali V, Landt M: Adipose tissue
leptin production and plasma leptin kinetics in humans. Diabetes
45: 984-987, 1996
[7] Flier JS: Clinical review 94: What's in a name? In search of
leptin's physiologic role. J Clin Endocrinol Metab 83: 1407-1413,
1998
[8] Janeckova R: The role of leptin in human physiology and patho-
physiology. Physiol Res 50: 443-459, 2001
[9] Moran O, Phillip M: Leptin: obesity, diabetes and other peripheral
effects--a review. Pediatr Diabetes 4: 101-109, 2003
[10] Baratta M: Leptin--from a signal of adiposity to a hormonal me-
diator in peripheral tissues. Med Sci Monit 8: RA282-292, 2002
[11] Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang
K: Structure-activity relationships of a synthetic pentapeptide that
specifically releases growth hormone in vitro. Endocrinology 106:
663-667, 1980
[12] Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA,
Rosenblum CI, et al.: A receptor in pituitary and hypothalamus
that functions in growth hormone release. Science 273: 974-977,
1996
[13] Bagnasco M, Kalra PS, Kalra SP: Ghrelin and leptin pulse dis-
charge in fed and fasted rats. Endocrinology 143: 726-729, 2002
[14] Korner J, Leibel RL: To eat or not to eat - how the gut talks to the
brain. N Engl J Med 349: 926-928, 2003
[15] De Ambrogi M, Volpe S, Tamanini C: Ghrelin: central and pe-
ripheral effects of a novel peptydil hormone. Med Sci Monit 9:
RA217-224, 2003
[16] Stamler J: Epidemic obesity in the United States. Arch Intern Med
153: 1040-1044, 1993
[17] Wickelgren I: Obesity: how big a problem? Science 280: 1364-
1367, 1998
[18] Reaven G: Metabolic syndrome: pathophysiology and implica-
tions for management of cardiovascular disease. Circulation 106:
286-288, 2002
[19] Hall JE, Brands MW, Dixon WN, Smith MJ Jr: Obesity-induced
hypertension. Renal function and systemic hemodynamics. Hyper-
tension 22: 292-299, 1993
[20] Carroll JF, Huang M, Hester RL, Cockrell K, Mizelle HL: Hemo-
dynamic alterations in hypertensive obese rabbits. Hypertension 26:
465-470, 1995
[21] Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini AJ: Clonidine
prevents insulin resistance and hypertension in obese dogs. Hyper-
tension 33: 548-553, 1999
[22] Jones DW, Kim JS, Andrew ME, Kim SJ, Hong YP: Body mass
index and blood pressure in Korean men and women: the Korean
National Blood Pressure Survey. J Hypertens 12: 1433-1437, 1994
[23] Garrison RJ, Kannel WB, Stokes J, 3rd, Castelli WP: Incidence
and precursors of hypertension in young adults: the Framingham
Offspring Study. Prev Med 16: 235-251, 1987
[24] Berchtold P, Jorgens V, Finke C, Berger M: Epidemiology of
obesity and hypertension. Int J Obes 5 suppl 1: 1-7, 1981
[25] Guyton AC: The surprising kidney-fluid mechanism for pressure
control--its infinite gain! Hypertension 16: 725-730, 1990
[26] Julius S, Valentini M, Palatini P: Overweight and hypertension : a
2-way street? Hypertension 35: 807-813, 2000
[27] Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G,
Baron AD: Obesity/insulin resistance is associated with endothe-
lial dysfunction. Implications for the syndrome of insulin resis-
tance. J Clin Invest 97: 2601-2610, 1996
[28] Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D,
Boone T, et al. Effects of the obese gene product on body weight
regulation in ob/ob mice. Science 269: 540-543, 1995
[29] Leibel RL, Chung WK, Chua SC Jr: The molecular genetics of
rodent single gene obesities. J Biol Chem 272: 31937-31940, 1997
[30] Agata J, Masuda A, Takada M, Higashiura K, Murakami H, Miya-
zaki Y, et al. High plasma immunoreactive leptin level in essential
hypertension. Am J Hypertens 10: 1171-1174, 1997
[31] Matsubara M, Chiba H, Maruoka S, Katayose S: Elevated serum
leptin concentrations in women with components of multiple risk
factor clustering syndrome. J Atheroscler Thromb 7: 231-237, 2000
The Emerging Roles of Leptin and Ghrelin Current Vascular Pharmacology, 2005, Vol. 3, No. 2 177
[32] Barba G, Russo O, Siani A, Iacone R, Farinaro E, Gerardi MC, et
al. Plasma leptin and blood pressure in men: graded association
independent of body mass and fat pattern. Obes Res 11: 160-166,
2003
[33] Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C,
et al. Hyperleptinemia as a component of a metabolic syndrome of
cardiovascular risk. Arterioscler Thromb Vasc Biol 18: 928-933,
1998
[34] Ruige JB, Dekker JM, Blum WF, Stehouwer CD, Nijpels G, Mooy
J, et al. Leptin and variables of body adiposity, energy balance, and
insulin resistance in a population-based study. The Hoorn Study.
Diabetes Care 22: 1097-1104, 1999
[35] Shintani M, Ikegami H, Fujisawa T, Kawaguchi Y, Ohishi M,
Katsuya T, et al. Leptin gene polymorphism is associated with hy-
pertension independent of obesity. J Clin Endocrinol Metab 87:
2909-2912, 2002
[36] Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lin-
dell K, et al. Hypertension in obesity and the leptin receptor gene
locus. J Clin Endocrinol Metab 85: 3126-3131, 2000
[37] Mallamaci F, Cuzzola F, Tripepi G, Cutrupi S, Parlongo S, Tripepi
R, et al. Gender-dependent differences in plasma leptin in essential
hypertension. Am J Hypertens 13: 914-920, 2000
[38] El-Gharbawy AH, Kotchen JM, Grim CE, Kaldunski M, Hoffmann
RG, Pausova Z, et al. Gender-specific correlates of leptin with hy-
pertension-related phenotypes in African Americans. Am J Hyper-
tens 15: 989-993, 2002
[39] Rutkowski MP, Klanke CA, Su YR, Reif M, Menon AG: Genetic
markers at the leptin (OB) locus are not significantly linked to hy-
pertension in African Americans. Hypertension 31: 1230-1234,
1998
[40] Hu FB, Chen C, Wang B, Stampfer MJ, Xu X: Leptin concentra-
tions in relation to overall adiposity, fat distribution, and blood
pressure in a rural Chinese population. Int J Obes Relat Metab Dis-
ord 25: 121-125, 2001
[41] Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role of
leptin and sympathetic nervous system. Am J Hypertens 14: 103S-
115S, 2001
[42] Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya
H, et al. Hemodynamic and hormonal effects of human ghrelin in
healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280:
R1483-1487, 2001
[43] Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA,
Ukkola O: Low plasma ghrelin is associated with insulin resis-
tance, hypertension, and the prevalence of type 2 diabetes. Diabetes
52: 2546-2553, 2003
[44] Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschop M,
Pasquali R: Plasma ghrelin, obesity, and the polycystic ovary syn-
drome: correlation with insulin resistance and androgen levels. J
Clin Endocrinol Metab 87: 5625-5629, 2002
[45] Poykko S, Ukkola O, Kauma H, Savolainen MJ, Kesaniemi YA:
Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and
hypertension in a random sample of middle-aged subjects. Diabe-
tologia 46: 455-458, 2003
[46] Haynes WG, Sivitz WI, Morgan DA, Walsh SA, Mark AL: Sym-
pathetic and cardiorenal actions of leptin. Hypertension 30: 619-
623, 1997
[47] Haynes WG, Morgan DA, Walsh SA, Sivitz WI, Mark AL: Car-
diovascular consequences of obesity: role of leptin. Clin Exp
Pharmacol Physiol 25: 65-69, 1998
[48] Casto RM, VanNess JM, Overton JM: Effects of central leptin
administration on blood pressure in normotensive rats. Neurosci
Lett 246: 29-32, 1998
[49] Lembo G, Vecchione C, Fratta L, Marino G, Trimarco V, d'Amati
G, et al. Leptin induces direct vasodilation through distinct endo-
thelial mechanisms. Diabetes 49: 293-297, 2000
[50] Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G,
Papapetropoulos A, Sessa WC, et al. Biological action of leptin as
an angiogenic factor. Science 281: 1683-1686, 1998
[51] Vecchione C, Maffei A, Colella S, Aretini A, Poulet R, Frati G, et
al. Leptin effect on endothelial nitric oxide is mediated through
Akt-endothelial nitric oxide synthase phosphorylation pathway.
Diabetes 51: 168-173, 2002
[52] Vecchione C, Aretini A, Maffei A, Marino G, Selvetella G, Poulet
R, et al. Cooperation between insulin and leptin in the modulation
of vascular tone. Hypertension 42: 166-170, 2003
[53] Fruhbeck G: Pivotal role of nitric oxide in the control of blood
pressure after leptin administration. Diabetes 48: 903-908, 1999
[54] Kuo JJ, Jones OB, Hall JE: Chronic cardiovascular and renal ac-
tions of leptin during hyperinsulinemia. Am J Physiol Regul Integr
Comp Physiol 284: R1037-1042, 2003
[55] Winters B, Mo Z, Brooks-Asplund E, Kim S, Shoukas A, Li D, et
al. Reduction of obesity, as induced by leptin, reverses endothelial
dysfunction in obese (Lep(ob)) mice. J Appl Physiol 89: 2382-
2390, 2000
[56] Mitchell JL, Morgan DA, Correia ML, Mark AL, Sivitz WI, Hay-
nes WG: Does leptin stimulate nitric oxide to oppose the effects of
sympathetic activation? Hypertension 38: 1081-1086, 2001
[57] Gardiner SM, Kemp PA, March JE, Bennett T: Regional haemo-
dynamic effects of recombinant murine or human leptin in con-
scious rats. Br J Pharmacol 130: 805-810, 2000
[58] Nakagawa K, Higashi Y, Sasaki S, Oshima T, Matsuura H, Cha-
yama K: Leptin causes vasodilation in humans. Hypertens Res 25:
161-165, 2002
[59] Matsuda K, Teragawa H, Fukuda Y, Nakagawa K, Higashi Y,
Chayama K: Leptin causes nitric-oxide independent coronary ar-
tery vasodilation in humans. Hypertens Res 26: 147-152, 2003
[60] Jalali A, Morgan DA, Sivitz WI, Correia ML, Mark AL, Haynes
WG: Does leptin cause functional peripheral sympatholysis? Am J
Hypertens 14: 615-618, 2001
[61] Shimokawa H, Yasutake H, Fujii K, Owada MK, Nakaike R, Fu-
kumoto Y, et al. The importance of the hyperpolarizing mechanism
increases as the vessel size decreases in endothelium-dependent
relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol
28: 703-711, 1996
[62] Brandes RP, Schmitz-Winnenthal FH, Feletou M, Godecke A,
Huang PL, Vanhoutte PM, et al. An endothelium-derived hyper-
polarizing factor distinct from NO and prostacyclin is a major en-
dothelium-dependent vasodilator in resistance vessels of wild-type
and endothelial NO synthase knockout mice. Proc Natl Acad Sci
USA 97: 9747-9752, 2000
[63] Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R:
Nitric oxide attenuates the release of endothelium-derived hyper-
polarizing factor. Circulation 94: 3341-3347, 1996
[64] Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kuni-
hiro I, et al. Hydrogen peroxide is an endothelium-derived hyper-
polarizing factor in human mesenteric arteries. Biochem Biophys
Res Commun 290: 909-913, 2002
[65] Bouloumie A, Marumo T, Lafontan M, Busse R: Leptin induces
oxidative stress in human endothelial cells. FASEB J 13: 1231-
1238, 1999
[66] Quehenberger P, Exner M, Sunder-Plassmann R, Ruzicka K,
Bieglmayer C, Endler G, et al. Leptin induces endothelin-1 in en-
dothelial cells in vitro. Circ Res 90: 711-718, 2002
[67] Fortuno A, Rodriguez A, Gomez-Ambrosi J, Muniz P, Salvador J,
Diez J, et al. Leptin inhibits angiotensin II-induced intracellular
calcium increase and vasoconstriction in the rat aorta. Endocrinol-
ogy 143: 3555-3560, 2002
[68] Shek EW, Brands MW, Hall JE: Chronic leptin infusion increases
arterial pressure. Hypertension 31: 409-414, 1998
[69] Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai
H, et al. Pathophysiological role of leptin in obesity-related hyper-
tension. J Clin Invest 105: 1243-1252, 2000
[70] Shek EW, Kim PK, Hall JE: Adrenergic blockade prevents leptin-
induced hypertension. FASEB J 1999: A456 (abst), 1999
[71] Sandoval DA, Davis SN: Leptin: metabolic control and regula-
tion. J Diabetes Complications 17: 108-113, 2003
[72] Tataranni PA: From physiology to neuroendocrinology: a reap-
praisal of risk factors of body weight gain in humans. Diabetes
Metab 24: 108-115, 1998
[73] Correia ML, Haynes WG: Leptin, obesity and cardiovascular
disease. Curr Opin Nephrol Hypertens 13: 215-223, 2004
[74] Eikelis N, Schlaich M, Aggarwal A, Kaye D, Esler M: Interactions
between leptin and the human sympathetic nervous system. Hy-
pertension 41: 1072-1079, 2003
[75] Paolisso G, Manzella D, Montano N, Gambardella A, Varricchio
M: Plasma leptin concentrations and cardiac autonomic nervous
system in healthy subjects with different body weights. J Clin En-
docrinol Metab 85: 1810-1814, 2000
[76] Tank J, Jordan J, Diedrich A, Schroeder C, Furlan R, Sharma AM,
et al. Bound leptin and sympathetic outflow in nonobese men. J
Clin Endocrinol Metab 88: 4955-4959, 2003
178 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
[77] Brabant G, Horn R, von zur Muhlen A, Mayr B, Wurster U, Hei-
denreich F, et al. Free and protein bound leptin are distinct and in-
dependently controlled factors in energy regulation. Diabetologia
43: 438-442, 2000
[78] Narkiewicz K, Kato M, Phillips BG, Pesek CA, Choe I, Winnicki
M, et al. Leptin interacts with heart rate but not sympathetic nerve
traffic in healthy male subjects. J Hypertens 19: 1089-1094, 2001
[79] Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M: Central
ghrelin modulates sympathetic activity in conscious rabbits. Hy-
pertension 40: 694-699, 2002
[80] Bisi G, Podio V, Valetto MR, Broglio F, Bertuccio G, Del Rio G,
et al. Acute cardiovascular and hormonal effects of GH and hex-
arelin, a synthetic GH-releasing peptide, in humans. J Endocrinol
Invest 22: 266-272, 1999
[81] Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F,
Takaya K, et al. Ghrelin, an endogenous growth hormone se-
cretagogue, is a novel orexigenic peptide that antagonizes leptin
action through the activation of hypothalamic neuropeptide Y/Y1
receptor pathway. Diabetes 50: 227-232, 2001
[82] Katugampola SD, Pallikaros Z, Davenport AP: [125I-His(9)]-
ghrelin, a novel radioligand for localizing GHS orphan receptors in
human and rat tissue: up-regulation of receptors with athersclero-
sis. Br J Pharmacol 134: 143-149, 2001
[83] Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H, Kan-
gawa K: Vasodilatory effect of ghrelin, an endogenous peptide
from the stomach. J Cardiovasc Pharmacol 39: 779-783, 2002
[84] Wiley KE, Davenport AP: Comparison of vasodilators in human
internal mammary artery: ghrelin is a potent physiological antago-
nist of endothelin-1. Br J Pharmacol 136: 1146-1152, 2002
[85] Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu
W, et al. Chronic administration of ghrelin improves left ventricu-
lar dysfunction and attenuates development of cardiac cachexia in
rats with heart failure. Circulation 104: 1430-1435, 2001
[86] Boger RH, Skamira C, Bode-Boger SM, Brabant G, von zur Mu-
hlen A, Frolich JC: Nitric oxide may mediate the hemodynamic ef-
fects of recombinant growth hormone in patients with acquired
growth hormone deficiency. A double-blind, placebo-controlled
study. J Clin Invest 98: 2706-2713, 1996
[87] Nagaya N, Kangawa K: Ghrelin, a novel growth hormone-
releasing peptide, in the treatment of chronic heart failure. Regul
Pept 114: 71-77, 2003
[88] Hall JE: Mechanisms of abnormal renal sodium handling in obe-
sity hypertension. Am J Hypertens 10: 49S-55S, 1997
[89] Hall JE: Pathophysiology of obesity hypertension. Curr Hypertens
Rep 2: 139-147, 2000
[90] Landsberg L, Krieger DR: Obesity, metabolism, and the sympa-
thetic nervous system. Am J Hypertens 2: 125S-132S, 1989
[91] Tuck ML, Sowers J, Dornfeld L, Kledzik G, Maxwell M: The
effect of weight reduction on blood pressure, plasma renin activity,
and plasma aldosterone levels in obese patients. N Engl J Med 304:
930-933, 1981
[92] Jackson EK, Li P: Human leptin has natriuretic activity in the rat.
Am J Physiol 272: F333-338, 1997
[93] Villarreal D, Reams G, Freeman RH, Taraben A: Renal effects of
leptin in normotensive, hypertensive, and obese rats. Am J Physiol
275: R2056-2060, 1998
[94] Carlyle M, Jones OB, Kuo JJ, Hall JE: Chronic cardiovascular and
renal actions of leptin: role of adrenergic activity. Hypertension
39: 496-501, 2002
[95] Villarreal D, Reams G, Freeman RH: Effects of renal denervation
on the sodium excretory actions of leptin in hypertensive rats. Kid-
ney Int 58: 989-994, 2000
[96] Beltowski J, G Wj, Gorny D, Marciniak A: Human leptin admin-
istered intraperitoneally stimulates natriuresis and decreases renal
medullary Na+, K+-ATPase activity in the rat -- impaired effect in
dietary-induced obesity. Med Sci Monit 8: BR221-229, 2002
[97] Coatmellec-Taglioni G, Dausse JP, Giudicelli Y, Ribiere C: Sexual
dimorphism in cafeteria diet-induced hypertension is associated
with gender-related difference in renal leptin receptor down-
regulation. J Pharmacol Exp Ther 305: 362-367, 2003
[98] Kim S, Whelan J, Claycombe K, Reath DB, Moustaid-Moussa N:
Angiotensin II increases leptin secretion by 3T3-L1 and human
adipocytes via a prostaglandin-independent mechanism. J Nutr 132:
1135-1140, 2002
[99] DiBona GF: Sympathetic nervous system and the kidney in hy-
pertension. Curr Opin Nephrol Hypertens 11: 197-200, 2002
[100] Rahmouni K, W GH: Leptin and the central neural mechanisms of
obesity hypertension. Drugs Today (Barc) 38: 807-817, 2002
[101] Matsumura K, Tsuchihashi T, Fujii K, Iida M: Neural regulation of
blood pressure by leptin and the related peptides. Regul Pept 114:
79-86, 2003
[102] Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD,
Haynes WG: Contrasting blood pressure effects of obesity in
leptin-deficient ob/ob mice and agouti yellow obese mice. J Hy-
pertens 17: 1949-1953, 1999
[103] Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL: Inter-
actions between the melanocortin system and leptin in control of
sympathetic nerve traffic. Hypertension 33: 542-547, 1999
[104] Correia ML, Morgan DA, Mitchell JL, Sivitz WI, Mark AL, Hay-
nes WG: Role of corticotrophin-releasing factor in effects of leptin
on sympathetic nerve activity and arterial pressure. Hypertension
38: 384-388, 2001
[105] Hausberg M, Morgan DA, Chapleau MA, Sivitz WI, Mark AL,
Haynes WG: Differential modulation of leptin-induced sympatho-
excitation by baroreflex activation. J Hypertens 20: 1633-1641,
2002
[106] Douglass J, McKinzie AA, Couceyro P: PCR differential display
identifies a rat brain mRNA that is transcriptionally regulated by
cocaine and amphetamine. J Neurosci 15: 2471-2481, 1995
[107] Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR,
et al. Leptin activates hypothalamic CART neurons projecting to
the spinal cord. Neuron 21: 1375-1385, 1998
[108] Matsumura K, Tsuchihashi T, Abe I: Central human cocaine- and
amphetamine-regulated transcript peptide 55-102 increases arterial
pressure in conscious rabbits. Hypertension 38: 1096-1100, 2001
[109] Matsumura K, Tsuchihashi T, Abe I: Central cardiovascular action
of neuropeptide Y in conscious rabbits. Hypertension 36: 1040-
1044, 2000
[110] Egawa M, Yoshimatsu H, Bray GA: Neuropeptide Y suppresses
sympathetic activity to interscapular brown adipose tissue in rats.
Am J Physiol 260: R328-334, 1991
[111] Vallejo M, Lightman SL: Pressor effect of centrally administered
neuropeptide Y in rats: role of sympathetic nervous system and
vasopressin. Life Sci 38: 1859-1866, 1986
[112] Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H:
Sympathetic and cardiovascular actions of orexins in conscious
rats. Am J Physiol 277: R1780-1785, 1999
[113] Matsumura K, Tsuchihashi T, Abe I: Central orexin-A augments
sympathoadrenal outflow in conscious rabbits. Hypertension 37:
1382-1387, 2001
[114] Lin Y, Matsumura K, Tsuchihashi T, Abe I, Iida M: Chronic cen-
tral infusion of orexin-A increases arterial pressure in rats. Brain
Res Bull 57: 619-622, 2002
[115] Chen CT, Hwang LL, Chang JK, Dun NJ: Pressor effects of orex-
ins injected intracisternally and to rostral ventrolateral medulla of
anesthetized rats. Am J Physiol Regul Integr Comp Physiol 278:
R692-697, 2000
[116] Machado BH, Bonagamba LG, Dun SL, Kwok EH, Dun NJ: Pres-
sor response to microinjection of orexin/hypocretin into rostral
ventrolateral medulla of awake rats. Regul Pept 104: 75-81, 2002
[117] Dun NJ, Le Dun S, Chen CT, Hwang LL, Kwok EH, Chang JK:
Orexins: a role in medullary sympathetic outflow. Regul Pept 96:
65-70, 2000
[118] Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Ta-
naka H, et al. Orexins and orexin receptors: a family of hypotha-
lamic neuropeptides and G protein-coupled receptors that regulate
feeding behavior. Cell 92: 573-585, 1998
[119] Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Ma-
tsukura S: Ghrelin acts in the central nervous system to stimulate
gastric acid secretion. Biochem Biophys Res Commun 280: 904-
907, 2001
[120] Matsumura K, Tsuchihashi T, Kagiyama S, Abe I, Fujishima M:
Subtypes of metabotropic glutamate receptors in the nucleus of the
solitary tract of rats. Brain Res 842: 461-468, 1999
[121] El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS:
Two defects contribute to hypothalamic leptin resistance in mice
with diet-induced obesity. J Clin Invest 105: 1827-1832, 2000
[122] Mark AL, Correia ML, Rahmouni K, Haynes WG: Selective leptin
resistance: a new concept in leptin physiology with cardiovascular
implications. J Hypertens 20: 1245-1250, 2002
The Emerging Roles of Leptin and Ghrelin Current Vascular Pharmacology, 2005, Vol. 3, No. 2 179
[123] Correia ML, Haynes WG, Rahmouni K, Morgan DA, Sivitz WI,
Mark AL: The concept of selective leptin resistance: evidence
from agouti yellow obese mice. Diabetes 51: 439-442, 2002
[124] Rahmouni K, Haynes WG, Morgan DA, Mark AL: Selective re-
sistance to central neural administration of leptin in agouti obese
mice. Hypertension 39: 486-490, 2002
[125] Wold LE, Relling DP, Duan J, Norby FL, Ren J: Abrogated leptin-
induced cardiac contractile response in ventricular myocytes under
spontaneous hypertension: role of Jak/STAT pathway. Hyperten-
sion 39: 69-74, 2002
[126] Packer M, Cohn J, editors: Consensus recommendations for the
management of chronic heart failure. American Journal of Cardiol-
ogy 83: 1A-38A. Suppl., 1999
[127] Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S,
Fubini A, et al. Ghrelin and des-acyl ghrelin inhibit cell death in
cardiomyocytes and endothelial cells through ERK1/2 and PI 3-
kinase/AKT. J Cell Biol 159: 1029-1037, 2002
[128] Locatelli V, Rossoni G, Schweiger F, Torsello A, De Gennaro
Colonna V, et al. Growth hormone-independent cardioprotective
effects of hexarelin in the rat. Endocrinology 140: 4024-4031, 1999
[129] Iglesias MJ, Pineiro R, Blanco M, Gallego R, Dieguez C, Gualillo
O, et al. Growth hormone releasing peptide (ghrelin) is synthesized
and secreted by cardiomyocytes. Cardiovasc Res 62: 481-488, 2004
[130] Pittman JG, Cohen P: The Pathogenesis of Cardiac Cachexia. N
Engl J Med 271: 403-409 CONTD, 1964
[131] Anker SD, Coats AJ: Cardiac cachexia: a syndrome with impaired
survival and immune and neuroendocrine activation. Chest 115:
836-847, 1999
[132] Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox
WJ, et al. Hormonal changes and catabolic/anabolic imbalance in
chronic heart failure and their importance for cardiac cachexia. Cir-
culation 96: 526-534, 1997
[133] Schulze PC, Kratzsch J, Linke A, Schoene N, Adams V, Gielen S,
et al. Elevated serum levels of leptin and soluble leptin receptor in
patients with advanced chronic heart failure. Eur J Heart Fail 5: 33-
40, 2003
[134] Richartz BM, Lotze U, Krack A, Gastmann A, Kuthe F, Figulla
HR: [Leptin: a parameter for metabolic changes in heart failure].
Z Kardiol 90: 280-285, 2001
[135] Wolk R, Johnson BD, Somers VK: Leptin and the ventilatory
response to exercise in heart failure. J Am Coll Cardiol 42: 1644-
1649, 2003
[136] O'Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith
PL: Leptin, obesity, and respiratory function. Respir Physiol 119:
163-170, 2000
[137] Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A,
Carella C, et al. Plasma leptin level is associated with myocardial
wall thickness in hypertensive insulin-resistant men. Hypertension
34: 1047-1052, 1999
[138] Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M: The
obesity-associated peptide leptin induces hypertrophy in neonatal
rat ventricular myocytes. Circ Res 93: 277-279, 2003
[139] Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare
JM: Disruption of leptin signaling contributes to cardiac hypertro-
phy independently of body weight in mice. Circulation 108: 754-
759, 2003
[140] Nickola MW, Wold LE, Colligan PB, Wang GJ, Samson WK, Ren
J: Leptin attenuates cardiac contraction in rat ventricular myocytes.
Role of NO. Hypertension 36: 501-505, 2000
[141] Illiano G, Naviglio S, Pagano M, Spina A, Chiosi E, Barbieri M, et
al. Leptin affects adenylate cyclase activity in H9c2 cardiac cell
line: effects of short- and long-term exposure. Am J Hypertens 15:
638-643, 2002
[142] Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J,
Gaw A, et al. Plasma leptin and the risk of cardiovascular disease
in the west of Scotland coronary prevention study (WOSCOPS).
Circulation 104: 3052-3056, 2001
[143] Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL: Leptin
enhances the calcification of vascular cells: artery wall as a target
of leptin. Circ Res 88: 954-960, 2001
[144] Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz
RS: Coronary artery calcium area by electron-beam computed to-
mography and coronary atherosclerotic plaque area. A histopa-
thologic correlative study. Circulation 92: 2157-2162, 1995
[145] Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire
J, Fitzpatrick LA, et al. Arterial calcification and not lumen steno-
sis is highly correlated with atherosclerotic plaque burden in hu-
mans: a histologic study of 723 coronary artery segments using
nondecalcifying methodology. J Am Coll Cardiol 31: 126-133,
1998
[146] Beadenkopf WG, Daoud AS, Love BM: Calcification in the Coro-
nary Arteries and Its Relationship to Arteriosclerosis and Myocar-
dial Infarction. Am J Roentgenol Radium Ther Nucl Med 92: 865-
871, 1964
[147] Loecker TH, Schwartz RS, Cotta CW, Hickman JR, Jr.: Fluoro-
scopic coronary artery calcification and associated coronary disease
in asymptomatic young men. J Am Coll Cardiol 19: 1167-1172,
1992
[148] Fitzgerald PJ, Ports TA, Yock PG: Contribution of localized cal-
cium deposits to dissection after angioplasty. An observational
study using intravascular ultrasound. Circulation 86: 64-70, 1992
[149] Stephenson K, Tunstead J, Tsai A, Gordon R, Henderson S, Dan-
sky HM: Neointimal formation after endovascular arterial injury is
markedly attenuated in db/db mice. Arterioscler Thromb Vasc Biol
23: 2027-2033, 2003
[150] Oda A, Taniguchi T, Yokoyama M: Leptin stimulates rat aortic
smooth muscle cell proliferation and migration. Kobe J Med Sci
47: 141-150, 2001
[151] Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell
JM: Endothelial dysfunction as a possible link between C-reactive
protein levels and cardiovascular disease. Clin Sci (Lond) 98: 531-
535, 2000
[152] Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ,
et al. Leptin regulates proinflammatory immune responses. FASEB
J 12: 57-65, 1998
[153] La Cava A, Matarese G: The weight of leptin in immunity. Nat
Rev Immunol 4: 371-379, 2004
[154] Maingrette F, Renier G: Leptin increases lipoprotein lipase secre-
tion by macrophages: involvement of oxidative stress and protein
kinase C. Diabetes 52: 2121-2128, 2003
[155] Kazumi T, Kawaguchi A, Hirano T, Yoshino G: C-reactive protein
in young, apparently healthy men: associations with serum leptin,
QTc interval, and high-density lipoprotein-cholesterol. Metabolism
52: 1113-1116, 2003
[156] Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, et
al. Ghrelin inhibits proinflammatory responses and nuclear factor-
kappaB activation in human endothelial cells. Circulation 109:
2221-2226, 2004
[157] Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expres-
sion of tumor necrosis factor-alpha: direct role in obesity-linked
insulin resistance. Science 259: 87-91, 1993
[158] Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW: C-reactive
protein in healthy subjects: associations with obesity, insulin re-
sistance, and endothelial dysfunction: a potential role for cytokines
originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:
972-978, 1999
[159] Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM,
Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-
6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol
Metab 82: 4196-4200, 1997
[160] Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S: Elabora-
tion of type-1 plasminogen activator inhibitor from adipocytes. A
potential pathogenetic link between obesity and cardiovascular dis-
ease. Circulation 93: 106-110, 1996
[161] Beaumont NJ, Skinner VO, Tan TM, Ramesh BS, Byrne DJ, Mik-
hailidis DP, et al. Ghrelin can bind to a species of high density
lipoprotein associated with paraoxonase. J Biol Chem 278: 8877-
8880, 2003
[162] Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis
of coronary artery disease and the acute coronary syndromes (2). N
Engl J Med 326: 310-318, 1992
[163] Loskutoff DJ, Samad F: The adipocyte and hemostatic balance in
obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 18: 1-6,
1998
[164] Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lens-
ing AW, et al. An association between atherosclerosis and venous
thrombosis. N Engl J Med 348: 1435-1441, 2003
[165] Wallaschofski H, Kobsar A, Sokolova O, Eigenthaler M, Lohmann
T: Co-activation of platelets by prolactin or leptin--
pathophysiological findings and clinical implications. Horm Metab
Res 36: 1-6, 2004
180 Current Vascular Pharmacology, 2005, Vol. 3, No. 2 Sharma and McNeill
[166] Nakata M, Yada T, Soejima N, Maruyama I: Leptin promotes
aggregation of human platelets via the long form of its receptor.
Diabetes 48: 426-429, 1999
[167] Konstantinides S, Schafer K, Koschnick S, Loskutoff DJ: Leptin-
dependent platelet aggregation and arterial thrombosis suggests a
mechanism for atherothrombotic disease in obesity. J Clin Invest
108: 1533-1540, 2001
[168] Bodary PF, Westrick RJ, Wickenheiser KJ, Shen Y, Eitzman DT:
Effect of leptin on arterial thrombosis following vascular injury in
mice. Jama 287: 1706-1709, 2002
[169] Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens
TW, Nyce MR, et al.: Serum immunoreactive-leptin concentra-
tions in normal-weight and obese humans. N Engl J Med 334: 292-
295, 1996
[170] Maruyama I, Nakata M, Yamaji K: Effect of leptin in platelet and
endothelial cells. Obesity and arterial thrombosis. Ann N Y Acad
Sci 902: 315-319, 2000
[171] Soderberg S, Olsson T, Eliasson M, Johnson O, Ahren B: Plasma
leptin levels are associated with abnormal fibrinolysis in men and
postmenopausal women. J Intern Med 245: 533-543, 1999
[172] Mutch NJ, Wilson HM, Booth NA: Plasminogen activator inhibi-
tor-1 and haemostasis in obesity. Proc Nutr Soc 60: 341-347, 2001
[173] Mertens I, Van Gaal LF: Obesity, haemostasis and the fibrinolytic
system. Obes Rev 3: 85-101, 2002
[174] Juhan-Vague I, Alessi MC: PAI-1, obesity, insulin resistance and
risk of cardiovascular events. Thromb Haemost 78: 656-660, 1997
[175] Skurk T, van Harmelen V, Lee YM, Wirth A, Hauner H: Relation-
ship between IL-6, leptin and adiponectin and variables of fibri-
nolysis in overweight and obese hypertensive patients. Horm Me-
tab Res 34: 659-663, 2002
[176] Sagawa N, Yura S, Itoh H, Mise H, Kakui K, Korita D, et al. Role
of leptin in pregnancy--a review. Placenta 23 Suppl A: S80-86,
2002
[177] Herran A, Garcia-Unzueta MT, Amado JA, de La Maza MT, Alva-
rez C, Vazquez-Barquero JL: Effects of long-term treatment with
antipsychotics on serum leptin levels. Br J Psychiatry 179: 59-62,
2001
[178] Malyszko J, Wolczynski S, Mysliwiec M: Leptin correlates with
some hemostatic parameters in CAPD patients. Nephron 92: 721-
724, 2002
[179] Soderberg S, Ahren B, Stegmayr B, Johnson O, Wiklund PG,
Weinehall L, et al. Leptin is a risk marker for first-ever hemor-
rhagic stroke in a population-based cohort. Stroke 30: 328-337,
1999
[180] Soderberg S, Stegmayr B, Ahlbeck-Glader C, Slunga-Birgander L,
Ahren B, Olsson T: High leptin levels are associated with stroke.
Cerebrovasc Dis 15: 63-69, 2003
[181] Thogersen AM, Soderberg S, Jansson JH, Dahlen G, Boman K,
Nilsson TK, et al. Interactions between fibrinolysis, lipoproteins
and leptin related to a first myocardial infarction. Eur J Cardiovasc
Prev Rehabil 11: 33-40, 2004
[182] The European Consensus Development Conference 2002: Sex
Steroids and Cardiovascular Diseases. On the route to combined
evidence from OC and HRT/ERT. Maturitas 44: 69-82, 2003
