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Chemical structure of lipoprotein(a) and plasminogen.
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High plasma concentrations of lipoprotein (a) [Lp(a)] are now considered a major risk factor for atherosclerosis and cardiovascular disease. This effect of Lp(a) may be related to its composite structure, a plasminogen-like inactive serine-proteinase, apoprotein (a) [apo(a)], which is disulfide-linked to the apoprotein B100 of an atherogenic low-de...
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Simple and precise methods for LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) measurements are essential for assessment of cardiovascular disease (CVD) risks and for lipid and lipoprotein studies. We report here an ultracentrifugation (UC) and HPLC method that requires substantially less specimen volume and provides the necessary reliability a...
Raised plasma lipoprotein(a) (lp(a)) concentrations have been reported in patients with Type I (insulin-dependent) diabetes mellitus, which were lowered by insulin therapy. To investigate the biochemical background of these changes, we studied the effect of insulin on apolipoprotein(a) (apo(a)) synthesis and mRNA levels in primary cultures of cynom...
Background:
Lipoprotein(a) (Lp(a)) is a causal risk factor for a variety of cardiovascular diseases. Apolipoprotein(a) (apo(a)), the distinguishing component of Lp(a), is homologous to plasminogen, suggesting that Lp(a) can interfere with the normal fibrinolytic functions of plasminogen. This has implications for the persistence of fibrin clots in...
To test directly whether fibrin(ogen) is a key binding site for apolipoprotein(a) [apo(a)] in vessel walls, apo(a) transgenic mice and fibrinogen knockout mice were crossed to generate fibrin(ogen)-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrin(ogen) deposition was found to be essentially col...
Lipoprotein Lp(a) is a major and independent genetic risk factor for atherosclerosis and cardiovascular disease. The essential difference between Lp(a) and low density lipoproteins (LDL) is apolipoprotein apo(a), a glycoprotein structurally similar to plasminogen, the precursor of plasmin, the fibrinolytic enzyme. This structural homology endows Lp...
Citations
... There is evidence that a substantial reduction of LP(a) can significantly prevent cardiovascular events [103], but current therapies targeted to reduce LP(a) are limited. Unlike traditional risk factors, there is a lack of strong evidence that diet or exercise can reduce LP(a) [104,105]. Statins and ezetimibe have been shown not to reduce LP(a) [106], and lipoprotein apheresis is not an appropriate approach [107]. Although PCSK9 inhibitors and lipoprotein replacement can partially reduce LP(a) [108], there is still a lack of cost-effective drugs. ...
Background
The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area.
Methods
The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel.
Result
A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies.
Conclusion
In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.
... 3,6,7 Lipoprotein(a), Lp(a), consists of a low-density lipoprotein (LDL)-like lipoprotein and apolipoprotein(a), apo(a): a glycoprotein, covalently linked via a disulfide bond. 8,9 Its LDL-like properties promote atherosclerosis, and its plasminogen-like apo(a) properties promote thrombosis by interfering with fibrinolysis. 8,9 An increased level of circulating Lp(a) is generally a risk factor for vascular diseases. ...
... 8,9 Its LDL-like properties promote atherosclerosis, and its plasminogen-like apo(a) properties promote thrombosis by interfering with fibrinolysis. 8,9 An increased level of circulating Lp(a) is generally a risk factor for vascular diseases. 10 Lipoprotein(a) is a candidate marker for the development of AAA. ...
... The evidence could stimulate further research on Lp(a) as a possible target for the management of AAA. Lipoprotein(a) is involved in both atherosclerosis and thrombosis, 8,9 and its high levels might contribute mechanistically to the development of AAA. The pathophysiologic role of Lp(a) in endothelial dysfunction, as an early step in atherogenesis, has been documented; for example, monocyte chemoattractant protein 1 (a molecule required for monocyte recruitment and migration across the endothelium) is carried by Lp(a). ...
BACKGROUND: Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a) (Lp(a)) is considered a candidate marker associated with the presence of AAA.
PURPOSE: The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA.
METHODS: A PubMed-based search was conducted up to April 30, 2015 to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics.
RESULTS: Overall, 9 studies with 1564 patients were included. The studies were published between 1988 and 2013, and were conducted in Sweden, USA, UK, Austria, Italy, and New Zealand. The mean age of the patients ranged from 56-73.5 years. The patients with AAA were found to have a significantly higher level of Lp(a) compared with the controls (SMD: 0.87, 95% CI: 0.41, 1.33, p < 0.001). This result remained robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies.
CONCLUSIONS: The present meta-analysis found a higher level of circulating Lp(a) in patients with AAA compared with controls. High Lp(a) levels can be associated with the presence of AAA and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA.
... Lp(a) are strong and independent risk factors for atherosclerotic cardiovascular disease [14][15][16][17][18][19][20]. The concentrations of Lp(a) in plasma vary over one thousand -fold between individuals, from < 0.2 to > 200 mg/dL. ...
The hypothesis is that poly-(R)-3-hydroxybutyrates (PHB), linear polymers of the ketone body, R-3-hydroxybutyrate (R-3HB), are atherogenic components of lipoprotein Lp(a). PHB are universal constituents of biological cells and are thus components of all foods. Medium chain-length PHB (<200 residues) (mPHB) are located in membranes and organelles, and short-chain PHB (<15 residues) are covalently attached to certain proteins (cPHB). PHB are highly insoluble in water, but soluble in lipids in which they exhibit a high intrinsic viscosity. They have a higher density than other cellular lipids and they are very adhesive, i.e. they engage in multiple noncovalent interactions with other molecules and salts via hydrogen, hydrophobic and coordinate bonds, thus producing insoluble deposits. Following digestive processes, PHB enter the circulation in chylomicrons and very low density lipoproteins (VLDL). The majority of the PHB (>70%) are absorbed by albumin, which transports them to the liver for disposal. When the amount of PHB in the diet exceed the capacity of albumin to safely remove them from the circulation, the excess PHB remain in the lipid core of LDL particles that become constituents of lipoprotein Lp(a), and contribute to the formation of arterial deposits. In summary, the presence of PHB - water-insoluble, dense, viscous, adhesive polymers - in the lipid cores of the LDL moieties of Lp(a) particles supports the hypothesis that PHB are atherogenic components of Lp(a).
... Plasma concentrations of Lp(a) are genetically determined and although there is considerable variation in circulating levels within the population (<10 to >100 mg/dL), levels remain relatively constant throughout an individual's lifetime. Unlike cholesterol, Lp(a) is resistant to modulation by lipid-lowering strategies such as statins or to lifestyle changes including diet, exercise or smoking (Pena Diaz et al., 2000). There are currently no specific and effective pharmacological therapeutics for Lp(a), indicating a clear rationale for their development (reviewed in Tsimikas and Hall, 2012). ...
... The structure of Lp(a) has been thoroughly described (Pena-Diaz et al., 2000), comprising an LDL-apoB-100 core covalently linked to apolipoprotein(a) (apo(a)). The copy number of kringle IV type 2 in apo(a) is variable and inversely correlated with Lp(a) plasma concentration ( Frank et al., 1996;Koschinsky et al., 1991). ...
Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin αVβ3-dependent, but transforming growth factor β-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, αVβ3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid-lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets.
... Many studies have been conducted on the pathophysiological role of Lp(a) in circulation. Although the findings are not exhaustive, it is well known that elevated plasma concentrations of Lp(a) (above 30mg/dl) and small dimensions of apo(a) are associated with increased risk of cardiovascular and cerebrovascular diseases [74,[77][78][79][80]. The size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk also for vascular dementia and AD [81]. ...
The barrier between blood and CSF contributes to homeostasis of the CNS and protects it from potentially harmful substances present in the blood. Lipoproteins present in the CSF are clearly distinct from their plasma counterparts. Human CSF lipoproteins contain mainly Apo AI and Apo E, the former deriving mostly from plasma after crossing the blood-cerebrospinal fluid barrier, the latter being also produced by CNS. Apo AI and E containing lipoproteins in the brain are key players in transport and delivery of lipids, cholesterol homeostasis, and are also involved in CNS remodeling mechanisms. On the other hand, the isoform apo E4 represents the most important genetic risk factor for sporadic and familial late-onset Alzheimer's disease and is involved in brain injury and neurodegenerative diseases. Apo B containing lipoproteins are not produced by CNS and the characterization of normal human CSF lipoproteins did not allowed the isolation of low density lipoproteins. Lipoprotein(a) is a low density lipoprotein-like particle with the unique protein apo(a), which is characterized by a dimensional polymorphism. Lipoprotein(a) is a well known risk factor for athero-thrombosis. The pathological role of Lipoprotein(a) is strictly associated with its plasma concentrations and the size of apo(a) isoforms, with inverse relation. The pathophysiology of Lipoprotein(a) in cardio and cerebrovascular system is widely studied. Recently, we demonstrated that, in neuroinflammatory and neurodegenerative disorders, Lipoprotein(a) can cross a dysfunctional blood-CSF barrier and be found in the CSF. This chapter focuses on the physiological presence of the lipoproteins in CNS, on the pathological aspects deriving from their isoforms, and in particular on the anomalous presence in CSF of Lipoprotein(a).
... The role of Lp(a) in atherothrombotic diseases is well known [7,8]. Both retrospective and prospective population studies have assessed high plasma Lp(a) (>30 mg/dl in many studies) as an independent risk factor for coronary heart diseases [CHD], myocardial infarction and ischaemic heart diseases [9-16], cerebrovascular disease [CVD], peripheral vascular diseases [17][18][19] and restenosis of coronary lesions [20]. ...
... 3 their high affinity to fibrin [8,44], are often associated with atherothrombotic diseases [45][46][47]. ...
Lipoprotein(a) is an LDL-like lipoparticle having the distinctive multi-kringle apolipoprotein(a). Although the physiological roles of lipoprotein(a) have been somewhat elusive, its pathological effects, closely related to plasma concentrations, have been widely studied. Several variants of the LPA gene contribute to its differential expression, and to lipoprotein(a) levels and pathogenicity. Although most of the variations in lipoprotein(a) concentrations are under genetic control, a relationship between plasma levels, apolipoprotein(a) phenotypes, anthropometric and biochemical factors, and environmental-associated events has been reported in many studies. Study of transgenic animals, which bypasses the absence of lipoprotein(a) in common laboratory animals, is an excellent model to examine the function of increased plasma lipoprotein(a) in differing pathological conditions or in cases of dietary intervention. This chapter offers an overview of some of the non-genetic factors which have modest, albeit significant, effects on lipoprotein(a) levels, also assessing their possible interactions with specific apolipoprotein(a) genotypes. The effects of estrogen-replacement therapy and dietary interventions in the modulation of lipoprotein(a) levels, and the influence of age are evaluated, taking into account their implications in the atherogenic risk. Lastly, the controversial role of lipoprotein(a) as an acute phase reactant and, in particular, its possible beneficial role in surgical trauma are discussed.
... 50 Plasma lipoprotein (a) levels Ͼ300 mg/L are significantly associated with venous thromboembolism (odds ratio, 2.1), and increased levels are also considered a risk factor for cardiovascular disease. 51,52 Plasminogen activator inhibitor-1 (PAI-1) is a serpin that down-regulates fibrinolysis. A deletion/insertion (4G/5G) polymorphism in its gene promoter region correlates with higher plasma levels. ...
Hypercoagulability, or thrombophilia, is a condition associated with an abnormally increased tendency toward blood clotting. Affected individuals are prone to developing venous or arterial thrombosis and often require thromboprophylaxis. Hypercoagulability can be generally classified as either an inherited or acquired condition. Patients with an inherited thrombophilia have genetic variances that alter the quality or quantity of proteins involved with hemostasis. Hypercoagulability may also be acquired and develop as an exaggeration of normal physiologic responses to major tissue injury, or an abnormal response to various prothrombotic clinical factors. Careful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. Heparin-induced thrombocytopenia is an example of an acquired hypercoagulable state that has been well studied and, when recognized, responds to appropriate therapy. In this article, we review the etiology, risks, and assessment of thrombophilia, with emphasis on the clinical lessons learned from heparin-induced thrombocytopenia.
... Lipoprotein(a) [Lp(a)] is a lipoparticle similar to a low-density lipoprotein (LDL), containing the exclusive apolipoprotein(a) [apo(a)], a multi-kringle molecule disulfide-linked to apolipoprotein B100 [1]. Although the atherothrombogenic features of plasma Lp(a) have been widely investigated [2][3][4], its physiological roles turn out to be more elusive. ...
To examine the role of lipoprotein(a) [Lp(a)] on the inflammatory response of cells in the nervous system by investigating its effect on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) secretion.
Human astrocytoma U373 cells were treated with recombinant apolipoprotein(a) [r-apo(a)] A10K (175-11 nM), alone or in combination with LPS (100 and 10 ng/ml). IL-6 levels were evaluated by immunoblotting. Statistical analysis was performed by one-way ANOVA.
r-apo(a) caused dose-dependent inhibition of LPS-induced IL-6 secretion (100 ng/ml LPS, p = 0.0205; 10 ng/ml LPS, p = 0.0005). Pre-treatment of cells with 88 nM r-apo(a), rinsing, and activation with 10 ng/ml LPS did not reverse the inhibition (p = 0.0048), which could be reversed by supplementation with excess serum (5-20%) (p = 0.0454) or recombinant CD14 (2.0-0.05 μg/ml) (p = 0.0230).
Our data indicate that apo(a) plays a natural anti-endotoxin role which relies on its interference with cell-associated and serum components of LPS signaling.
... The available literature does not mention comparable studies using dyslipidemic patients such as those examined by us. It is known that lipoprotein (a), due to its structural resemblance of plasminogen, competes with it for the linkage to the lysine residues exposed on fibrin (32,33); thus, a slower lysis of the fibrin network of such patients is to be expected. Furthermore, the high lipid content reduced the pore size of the fibrin network, reflected in the diminished permeation values. ...
Individuals with hypertension, dyslipidemia or diabetes are at a higher risk to suffer cardiovascular disease than other people; while impaired fibrin structure/function may contribute to further raise the cardiovascular risk in the former. The purpose of this work was to study the fibrin network and fibrin degradation properties in hypertensive (HT) patients, pharmacologically treated, 124 +/- 11 mmHg, systolic blood pressure, and 70 +/- 10 mmHg, diastolic blood pressure, n = 12; metabolic dyslipidemic patients (DL), cholesterol: 5.7 +/- 1.5 mmol/L, n = 10; patients with type 2 diabetes mellitus (T2D), fasting plasma glucose: 8.8 +/- 2.2 mmol/L, n = 10; and a control group of healthy individuals, n = 9. The fibrinogen concentration was determined by the gravimetric method. Fibrin network formation and porosity were assessed by turbidity and permeation techniques, respectively; fibrin elastic properties were evaluated by compaction and fibrin lysis, by turbidity after addition of external tPA prior to plasma clotting. Fibrinogen concentration was significantly higher only in T2D patients (p = 0.004), compared to the control group. The fibrin polymerization and lysis processes were similar for all patient and control groups. Permeation was significantly slower in DL and T2D patients, p = 0.022 and 0.0002, respectively, whereas the compaction coefficient was significantly smaller in T2D patients, p = 0.0015. Our results suggest that the fibrin structure was altered in DL and T2D patients, probably due to the increased cholesterol and glycation, respectively.
... KIV type 1 and KIV type 3 to KIV type 10 are present in single copies whereas KIV type 2 varies in number given rise to more than 30 apo(a) isoforms (Marcovina et al., 1993). Since KIV type 10 contains a fibrin-binding site functionally identical to kringle 4 of plasminogen, and the protease region of apo(a) is inactive, Lp(a) may compete with plasminogen for binding to fibrin and inhibit fibrinolysis (De la Peña Diaz et al., 2000). In summary, kringle KIV is the major basic structural unit of apo(a), which defines both its molecular size polymorphism and pathophysiological properties shared with Lp(a). ...
Lp(a) is a lipoparticle of unknown function mainly present in primates and humans. It consists of a low-density lipoprotein and apo(a), a polymorphic glycoprotein. Apo(a) shares sequence homology and fibrin binding with plasminogen, inhibiting its fibrinolytic properties. Lp(a) is considered a link between atherosclerosis and thrombosis. Marked inter-ethnic differences in Lp(a) concentration related to the genetic polymorphism of apo(a) have been reported in several populations.
The study examined the structural and functional features of Lp(a) in three Native Mexican populations (Mayos, Mazahuas and Mayas) and in Mestizo subjects.
We determined the plasma concentration of Lp(a) by immunonephelometry, apo(a) isoforms by Western blot, Lp(a) fibrin binding by immuno-enzymatic assay and short tandem repeat (STR) polymorphic marker genetic analysis by capillary electrophoresis.
Mestizos presented the less skewed distribution and the highest median Lp(a) concentration (13.25 mg dL(-1)) relative to Mazahuas (8.2 mg dL(-1)), Mayas (8.25 mg dL(-1)) and Mayos (6.5 mg dL(-1)). Phenotype distribution was different in Mayas and Mazahuas as compared with the Mestizo group. The higher Lp(a) fibrin-binding capacity was found in the Maya population. There was an inverse relationship between the size of apo(a) polymorphs and both Lp(a) levels and Lp(a) fibrin binding.
There is evidence of significative differences in Lp(a) plasma concentration and phenotype distribution in the Native Mexican and the Mestizo group.
