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Thrombus formation by EMP in vivo. EMP from unstimulated and IL-1activated endothelial cells (48 hours) were injected into rats to assess their ability to trigger thrombus formation in vivo. EMP fractions from three different endothelial cell cultures were used. From each individual culture, EMP from unstimulated endothelial cells were injected into 2 rats (EMP-IL-1). From the corresponding EMP of activated cells, EMP not preincubated with antibodies (EMP + IL-1) were injected into 2 rats, EMP preincubated with anti-human TF (EMP+anti-TF) in 2 rats, and EMP preincubated with anti-human factor XII (EMP+anti-FXII) also in 2 rats. Thrombus weights for
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Statins reduce cardiovascular disease risk and affect endothelial function by cholesterol-dependent and independent mechanisms. Recently, circulating (detached) endothelial cells and endothelial microparticles (EMP) have been associated with endothelial functioning in vitro and in vivo. We investigated whether simvastatin affects endothelial detach...
Citations
... Our results showing that the senolytic effect of statins could be blunted by the concomitant administration of mevalonic acid are in agreement with the observations of other research groups who showed that the apoptotic effect of statins on various tumor cells and endothelial cells was also prevented with the concomitant administration of mevalonic acid. Mevalonate, the synthesis of which can be directly inhibited by statins, is not only required for cholesterol production but is also important for the synthesis of sterol products such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate; which deficiency is associated with statin-mediated apoptosis induction in endothelial cells [51,56]. It has been shown repeatedly that the prenylation of small G proteins such as RhoA, which are important for cell adhesion, is negatively influenced by statin administration. ...
... Using bright-field time-lapse video microscopy, we first showed that cells exposed to senolytic concentrations of simvastatin initially contract, then detach from the matrix, and subsequently show membrane blebbing, followed by apparent cell death. Such cell detachment is consistent with a previous report describing the detachment of healthy proliferative HUVECs in response to 1 or 5 µM simvastatin treatment [56]. Yet, although the authors of this study suggested that simvastatin fosters cell detachment by inhibiting prenylation and presumably caspase-8 activation, they acknowledged an open question: whether caspase activation precedes detachment or is a consequence thereof [56]. ...
... Such cell detachment is consistent with a previous report describing the detachment of healthy proliferative HUVECs in response to 1 or 5 µM simvastatin treatment [56]. Yet, although the authors of this study suggested that simvastatin fosters cell detachment by inhibiting prenylation and presumably caspase-8 activation, they acknowledged an open question: whether caspase activation precedes detachment or is a consequence thereof [56]. This question was addressed by our approach, where we visualized caspase activation in real-time using a fluorescent caspase-3/7 sensor. ...
Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of these cells has been shown to improve the health of aged experimental animals, leading to a clinical interest in finding compounds that selectively eliminate senescent cells while sparing non-senescent ones. In our study, we identified a senolytic capacity of statins, which are lipid-lowering drugs prescribed to patients at high risk of cardiovascular events. Using two different models of senescence in human vascular endothelial cells (HUVECs), we found that statins preferentially eliminated senescent cells, while leaving non-senescent cells unharmed. We observed that the senolytic effect of statins could be negated with the co-administration of mevalonic acid and that statins induced cell detachment leading to anoikis-like apoptosis, as evidenced by real-time visualization of caspase-3/7 activation. Our findings suggest that statins possess a senolytic property, possibly also contributing to their described beneficial cardiovascular effects. Further studies are needed to explore the potential of short-term, high-dose statin treatment as a candidate senolytic therapy.
... 192 Regarding the cornerstone drug for LLT, on one hand statins could increase EV release in in vitro and in vivo studies. 193,194 In contrast, a plethora of studies described the opposite. [195][196][197][198][199] Pravastatin and simvastatin decreased pEVs in type 2 diabetic 196,200 and hypertensive patients. ...
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up‐to‐date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.
... This is found to be modulated via a reduction in phosphorylation and activation of endothelial nitric oxide synthase [26], regional oxidative stress [27], or an enhanced NADPH oxidase activity [28], leading to impaired vascular relaxation abilities. In contrast, other studies reported that endothelial-derived EVs promote blood vessel regeneration and vascular protection [29]. Endothelial EVs containing caspase-3 secrete the cargo, which reduces intracellular levels of this proapoptotic protein [29]. ...
... In contrast, other studies reported that endothelial-derived EVs promote blood vessel regeneration and vascular protection [29]. Endothelial EVs containing caspase-3 secrete the cargo, which reduces intracellular levels of this proapoptotic protein [29]. Additionally, annexin I/phosphatidylserine receptor-dependent EVs can protect endothelial cells (ECs) from apoptosis [30]. ...
Extracellular vesicles are heterogeneous structures surrounded by cell membranes and carry complex contents including nucleotides, proteins, and lipids. These proteins include cytokines and chemokines that are important for exaggerating local and systemic inflammation in disease. Extracellular vesicles are mainly categorized as exosomes and micro-vesicles, which are directly shed from the endosomal system or originated from the cell membrane, respectively. By transporting several bioactive molecules to recipient cells and tissues, extracellular vesicles have favorable, neutral, or detrimental impacts on their targets, such as switching cell phenotype, modulating gene expression, and controlling biological pathways such as inflammatory cell recruitment, activation of myeloid cells and cell proliferation. Extracellular vesicles mediate these functions via both autocrine and paracrine signaling. In the cardiovascular system, extracellular vesicles can be secreted by multiple cell types like cardiomyocytes, smooth muscle cells, macrophages, monocytes, fibroblasts, and endothelial cells, and affect functions of cells or tissues in distant organs. These effects involve maintaining homeostasis, regulating inflammation, and triggering pathological process in cardiovascular disease. In this review, we mainly focus on the role of micro-vesicles and exosomes, two important subtypes of extracellular vesicles, in local and systemic inflammation in cardiovascular diseases such as myocardial infarction, atherosclerosis and heart failure. We summarize recent findings and knowledge on the effect of extracellular vesicles in controlling both humoral and cellular immunity, and the therapeutic approaches to harness this knowledge to control exacerbated inflammation in cardiovascular diseases.
... Indeed, endothelial EV carrying EPCR and activated protein C (APC) could also promote cell survival by induction of cytoprotective and anti-inflammatory effects [60]. Furthermore, endothelial cells in culture could release EV containing caspase-3 and 8 [61]. Statins, a treatment to reduce CVD risks, increase the detachment of apoptotic cells and release of endothelial MVs. ...
... Thus, endothelial-derived MVs contribute to the sorting of several pro-apoptotic factors preventing cell detachment and apoptosis. This mechanism could explain the statins protective effect on the endothelium [61]. EVs from apoptotic platelets induce monocyte adhesion, and polarization into resident phagocyte macrophage [62]. ...
Extracellular vesicles (EVs) are small vesicles released by the majority of cells in response to cell activation or death stimuli. They are grouped as small EVs or exosomes, large EVs such as microvesicles (MVs) and apoptotic bodies, resulting from distinct mechanisms of generation. EVs are released into the extracellular space, in most human biological fluids and tissues, including atherosclerotic plaques. They transport complex cargo of bioactive molecules, including proteins, lipids and genetic material and are therefore involved in pathophysiological pathways of cell-cell communication. Indeed, EVs are involved in several processes such as inflammation, coagulation, vascular dysfunction, angiogenesis and senescence, contributing to the initiation and progression of atherothrombotic diseases. Consequently, they behave as a determinant of atherosclerotic plaque vulnerability leading to major cardiovascular disorders. Over the last decade, the field of EVs research has grown, highlighting their involvement in atherosclerosis. However, limitations in both detection methodologies and standardisation have hindered implementation of EVs in the clinical settings. This review summarizes the effect of EVs in atherosclerosis development, progression and severity, with specific attention devoted to their ambivalent roles in senescence and hemostasis. This review will also highlight the role of MVs as multifaceted messengers, able to promote or to attenuate atherosclerosis progression. Finally, we will discuss the main technical challenges and prerequisites of standardization for driving EVs to the clinics and delineate their relevance as emergent biomarkers and innovative therapeutic approaches in atherosclerosis.
... For example, in addition to their prescribed daily medications, NSTEMI patients were provided with medications to treat the acute MI upon arrival to the emergency room and before cardiac catheterization procedures took place. There have been previous reports of clinically relevant concentrations of statins increasing MP concentrations using a cell culture model (Diamant et al., 2008), while other studies have found that statins and calcium channel blockers F I G U R E 1 Comparison of CD31+/CD42b− (a), CD62E+ (b), and CD34+ (c) microparticle (MP) concentrations in healthy adults (n = 15), coronary artery disease (CAD; n = 10), and non-ST elevation myocardial infarction (NSTEMI; n = 13). CD62E+ MPs are depicted after covarying for triglycerides and systolic blood pressure. ...
Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies.
Purpose:
To quantify plasma concentrations of CD31+/CD42b-, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non-ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60-75 years old.
Methods:
CD31+/CD42b-, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed.
Results:
Concentrations of CD31+/CD42b- MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03).
Conclusions:
Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b- MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations.
... By facilitating endothelial cell-derived EV release, this pleiotropic effect of statins may improve the overall condition of the remaining vascular endothelium. 101 However, the reports exploring the impact of statins on EV release are still a matter of debate: in vitro data showed that statins exerted anti-inflammatory effects on endothelial cells and decreased vesiculation processes by inhibiting the Rho-kinase pathway. 102,103 In line with these rather contradictory in vitro findings, clinical studies reported conflicting results exploring the effect of statins on endothelial-and platelet-derived EVs. ...
Extracellular vesicles originate from diverse subcellular compartments and are released in the extracellular space. By transferring their cargoes into target cells and tissues, they now emerge as novel regulators of intercellular communication between adjacent and remote cells. Because vesicle composition and biological content are specific signatures of cellular activation and injury, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Characterization of circulating vesicles- or nonvesicles-bound nucleic acids represents a valuable tool for diagnosing and monitoring cardiovascular diseases, recently referred to as a liquid biopsy. Circulating extracellular vesicles offer a noninvasive and almost continuous access to circulating information on the disease state in epidemiological investigations. Finally, genetic engineering and cell-specific application of extracellular vesicles could display a novel therapeutic option for the treatment of cardiovascular diseases. In this review, we summarize the current knowledge about extracellular vesicles as diagnostic and prognostic biomarkers, as well as their potential applications for longitudinal epidemiological studies in cardiovascular diseases.
... The effects of statins are more debated. In vitro data show that statins might exert an antiinflammatory effect on endothelial cells and decrease their vesiculation via inhibition of the Rhokinase pathway 5,198 , whereas other studies show increased endothelial cell vesiculation through prenyl ation inhibition 199 . Similar conflicting results on the effect of statin treatment on circulating endothelial and platelet microvesicles were obtained in patients 84,[200][201][202][203][204] . ...
Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.
... It has been shown, that combination of simvastatin with losartan, an angiotensin II receptor antagonist used in the treatment of hypertension, diminished monocyte-derived MP, EMP and PMP levels in patients with hypertension and type 2 diabetes [175,176]. One in vitro study has reported that physiologically significant concentrations of simvastatin enhanced apoptotic HU-VEC detachment and MP generation by protein prenylation repression, probably through caspase-8 [177]. The EMP increasing after statin treatment may reflect statins' ability to improve the general state of endothelium by facilitating apoptotic cell detachment and MP release. ...
Cardiovascular diseases (CVD) are the main object of morbidity and death in the world. There are different triggers of CVD, but atherosclerosis and/or hypertension are the most usual. CVD risk factors are used as prognosticators of disease process, while the biomarkers that envisage cardiovascular risk have an important biological basis. The integration of CVD risk factors and new biomarkers can improve CVD risk stratification and disease management. The identification of microparticles (MPs) in body fluids has opened new perspectives in diagnosis, prognosis and therapy of CVD pathogenesis. MPs are submicron vesicles released from a diversity of cell types with pleiotropic biological effects on signaling among cells. They are correlated with disease state and play a major role in atherosclerosis associated with inflammation, thrombosis as well as in CVD development and progression. This review reveals many sides of MPs as risk factors, biomarkers, novel forms of intercellular communication, non-invading potential diagnostic tools and discusses their positive and negative impact on CVD.
... This indicates that MP release provides a means of preventing the buildup of caspases in the cell that can trigger apoptosis in the cells. This idea has been further validated by Diamant et al. who showed that adding simvastatin to human endothelial cell cultures had no effect on cell viability, while they observed a significant release of MPs that contained caspase-3 [29]. This indicated that packing and clearance of excess caspase-3 via MPs improves or sustains cell viability. ...
Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular ‘trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in ‘liquid biopsy’ approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer’s disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases.
... However, in Diamant et al. study such interaction had been observed, indeed after statin therapy, the number of endothelial microparticles in diabetic and hypertensive subjects was declined. [29] Accordingly, this would be a further support to our findings, so some variables including cardiovascular event history, hyperlipidemia, and statin therapy remain significant independent predictors of CD34 + CD309 level in TIA patients. However, cardiovascular event history and hyperlipidemia act as nonsignificant risk factors, but statin therapy proceeds as a protective factor for recurrence of TIA. ...
Background
The role of endothelial progenitor cells (EPCs) in the maintenance of vascularization following ischemic brain after experimental stroke has been established. Accordingly, in this study, we evaluated the role of circulating EPCs in transient ischemic attack (TIA) patients for future cerebrovascular (CV) events.
Materials and Methods
The level of circulating EPCs (staining markers: CD34, CD309) were determined using flow cytometry at 24 h after TIA in thirty consecutive patients. The EPCs level was also evaluated once in thirty healthy volunteers. Over a period of 12 months, all patients were evaluated by an experienced neurologist for recurrent TIA, stroke or death induced by CV disorders.
Results
Circulating EPCs increased in patients group following the first attack of TIA when compared with controls. By analysis of covariance, cardiovascular event history, hyperlipidemia, and statin therapy remained significant independent predictors of EPCs. The mean (standard deviation) duration of follow-up was 10.5 (3.1) months (range, 2–12 months). During follow-up, a total of three patients died due to CV accident and four patients experienced again recurrent TIA. By analyzing data with Cox regression, EPC did not predict the future CV events in TIA patients.
Conclusion
Increased incidence of future CV events did not occur in those patients with elevated EPCs in the first attack of TIA. The significant predicting factors of EPCs were cardiovascular event history, hyperlipidemia, and statin therapy.
