The term extracellular vesicles (EVs) describes membrane vesicles released into the extracellular space by most cell types. EVs have been recognized to play an important role in cell-to-cell ...communication. They are known to contain various bioactive molecules, including proteins, lipids, and nucleic acids. Although the nomenclature of EVs is not entirely standardized, they are considered to include exosomes, microparticles or microvesicles and apoptotic bodies. EVs are believed to play important roles in a wide range of biological processes. Although the pathogenic roles of EVs are largely documented, their protective roles are not as well established. Cardiovascular disease represents one of the most relevant and rapidly growing areas of the EV research. Circulating EVs released from platelets, erythrocytes, leukocytes, and endothelial cells may contain potentially valuable biological information for biomarker development in cardiovascular disease and could serve as a vehicle for therapeutic use. Herein, we provide an overview of the current knowledge in EV in cardiovascular disease, including a discussion on challenges in EV research, EV properties in various cell types, and their importance in atherosclerotic disease.
•Extracellular vesicles (EVs) play an important role in cell-cell communication.•EVs contain bioactive molecules including proteins, lipids, and nucleic acids.•EVs are released from monocytes/macrophages, endothelial cells and platelets.•Challenges include lack of standardization of isolation techniques and protocols.•EVs may serve as markers in cardiovascular disease and vehicles for therapeutic use.
Cholesterol efflux is the initial step in the reverse cholesterol transport pathway by which excess cholesterol in peripheral cells is exported and subsequently packaged into high-density lipoprotein ...(HDL) particles. Adiponectin is the most abundantly secreted adipokine that possesses anti-inflammatory and vasculoprotective properties via interaction with transmembrane receptors, AdipoR1 and AdipoR2. Evidence suggests that low levels of adiponectin may be a useful marker for atherosclerotic disease. A proposed anti-atherogenic mechanism of adiponectin involves its ability to promote cholesterol efflux. We performed a systematic review of the role of adiponectin in cholesterol efflux and HDL biogenesis, and of the proteins and receptors believed to be implicated in this process. Nineteen eligible studies (7 clinical, 11 fundamental, 1 clinical + fundamental) were identified through Ovid Medline, Ovid Embase, and Pubmed, that support the notion that adiponectin plays a key role in promoting ABCA1-dependent cholesterol efflux and in modulating HDL biogenesis via activation of the PPAR-γ/LXR-α signalling pathways in macrophages. AdipoR1 and AdipoR2 are suggested to also be implicated in this process, however the data are conflicting/insufficient to establish any firm conclusions. Once the exact mechanisms are unravelled, adiponectin may be critical in defining future treatment strategies directed towards increasing HDL functionality and ultimately reducing atherosclerotic disease.
•Circulating adiponectin is independently associated with increased cholesterol efflux.•Adiponectin promotes apoA-I/HDL-mediated cholesterol efflux via ABCA1 in liver/macrophage.•The effect of adiponectin on ABCG1- or SR-B1-dependent efflux remains inconclusive.•PPAR-ɣ and LXR-α are suggested to be implicated in adiponectin's effects on efflux.•Adiponectin's effects may be mediated by AdipoR1/AdipoR2 but conflicting data exist.
Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and ...progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology.
Potential therapeutic targets for NLRP3 inflammasome blockage to interleukin-1 to interleukin-6 signaling pathway. Extracellular stimulus, crystalline structures (including cholesterol crystals), ATP and K+ efflux through the ATP-gated P2X7 channel can activate NLRP3 inflammasome. NLRP3 activation leads to active caspase-1, which cleaves the proforms of IL-1β and IL-18 into their mature forms. This result in production of pro-IL-1β to IL-1β with consequent downstream effects on IL-6. Several agents have been studied targeting different components of the NLRP3 inflammasome pathway. Potential interventions include canakinumab, anakinra, tocilizumab, methotrexate, and colchicine. MCC950 could inhibit ATPase activity of NLRP3 and inhibit NLRP3 oligomerization. Colchicine and MCC950 block NLRP3 inflammasome activation through disruption of ASC oligomerization. Colchicine could also halt lysosome damage and P2X7 receptor activity, and consequently, prevent NLRP3 inflammasome activation. Canakinumab block IL-1β. Statins, as substrates for organic anion transporting polypeptide (OATP) transporter, decrease cellular cholesterol production through inhibition of mevalonate conversion, which results in suppression of the TLR4/MyD88/NF-ĸB signaling pathway and a reduction in the formation of the NLRP3 complex. Display omitted
Abstract
Stroke is a leading cause of death and disability worldwide. Women are disproportionately affected by stroke, exhibiting higher mortality and disability rates post-stroke than men. Clinical ...stroke research has historically included mostly men and studies were not properly designed to perform sex- and gender-based analyses, leading to under-appreciation of differences between men and women in stroke presentation, outcomes, and response to treatment. Reasons for these differences are likely multifactorial; some are due to gender-related factors (i.e. decreased social support, lack of stroke awareness), yet others result from biological differences between sexes. Unlike men, women often present with ‘atypical’ stroke symptoms. Lack of awareness of ‘atypical’ presentation has led to delays in hospital arrival, diagnosis, and treatment of women. Differences also extend to carotid atherosclerotic disease, a cause of stroke, where plaques isolated from women are undeniably different in morphology/composition compared to men. As a result, women may require different treatment than men, as evidenced by the fact that they derive less benefit from carotid revascularization than men but more benefit from medical management. Despite this, women are less likely than men to receive medical therapy for cardiovascular risk factor management. This review focuses on the importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease, summarizing the current evidence with respect to (i) stroke incidence, mortality, awareness, and outcomes, (ii) carotid plaque prevalence, morphology and composition, and gene connectivity, (iii) the role of sex hormones and sex chromosomes in atherosclerosis and ischaemic stroke risk, and (iv) carotid disease management.
Graphical Abstract
Graphical Abstract
Summary of differences between women and men at the pre-stroke, stroke management, and outcome level. All differences listed are described as observed in women. Blue text indicates where gender may play a role. CEA, carotid endarterectomy; tPA, tissue plasminogen activator. Created with BioRender.com.
Sex-specific differences in plaque composition and instability underscore the need to explore circulating markers for better prediction of high-risk plaques. This cross-sectional study aims to (1) ...investigate differences in lipid, immune, and adipokine circulating profiles between men and women with stable versus unstable plaques and (2) identify circulating markers that can better classify men and women according to plaque instability.
Preoperative blood samples and plaque specimens were collected from consecutive men and women with carotid artery stenosis ≥50% and who underwent a carotid endarterectomy between 2009 and 2018. Adipokine, lipid, and immune profiling was conducted. Plaque stability was determined by gold-standard histological classifications. Statistical analyses, including χ
, ANOVA, Kruskal-Wallis, and logistic regression, assessed differences in plaque features and blood parameters between men and women with stable and unstable plaques.
Of 470 recruited patients (aged 70.8±9.2 years), the final study analyses included 317 men and 143 women (aged 71.0±9.0 years). Men exhibited more unstable plaques (
<0.001), characterized by increased plaque hemorrhage, larger lipid core, and inflammation (
<0.001), along with less favorable circulating profiles. Antagonistic interactions between sex and white blood cell (WBC) counts, basophil-to-WBC ratio, and platelet counts influenced plaque instability. In men, low WBC counts, high monocyte-to-WBC ratio, low basophil-to-WBC ratio, and high LDL-C (low-density lipoprotein cholesterol) levels were associated with greater plaque instability (odds ratio, 0.827 95% CI, 0.713-0.926, 1.158 95% CI, 1.027-1.305, 0.495 95% CI, 0.281-0.871, and 1.564 95% CI, 1.001-2.443, respectively) and more unstable features (ie, inflammation, foam cells, and neovascularization). In women, a high basophil-to-WBC ratio was associated with greater plaque instability (3.142 95% CI, 1.220-8.093), hemorrhage, and thrombosis, while a high molecular weight-to-total adiponectin ratio was associated with decreased instability (0.014 95% CI, 0.000-0.646) and inflammation.
Our findings demonstrated sex-specific differences, with women displaying more stable plaque phenotypes and favorable circulating profiles compared with men. This proof-of-concept study was also designed as the key first step in exploring novel sex-specific associations between circulating lipid, immune, and adipokine profiles and carotid plaque instability.
The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to ...monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.
Abstract New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in ...the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.
Among adiponectin's beneficial properties is its ability to promote cellular cholesterol efflux, thereby generating high-density lipoprotein (HDL) particles. However, adiponectin's role in the ...regulation of macrophage lipid metabolism, a crucial process in atherogenesis, remains poorly investigated. The aim of this study was to characterize the adiponectin's role in HDL biogenesis.
We perform kinetics studies in baby hamster kidney (BHK) and Tamm-Horsfall protein 1 (THP-1) cell lines to elucidate adiponectin's role in HDL biogenesis. In cholesterol-enriched cells, specific molar doses of adiponectin stimulated cholesterol efflux with high efficiency to apoA-I. In the presence of adiponectin, BHK cells expressing ATP binding cassette transporter A1 (ABCA1) or ABCG1 generated lipidated particles having α electrophoretic mobility (α-HDL) and a molecular size of 7.5–20 nm. Interestingly, in THP-1 macrophages, cholesterol efflux was associated with more lipidated preβ1-HDL particles. Direct molecular interaction of adiponectin with apoA-I enhanced the affinity of apoA-I to free cholesterol and resulted in an increase in preβ1-HDL particles from plasma ex vivo. Adiponectin increased ABCA1 and ABCG1 protein expression and activated the formation of ABCA1-linked cholesterol oxidase sensitive plasma membrane domains.
Adiponectin upregulated ABCA1 and ABCG1 protein expression, reduced lipid accumulation, and efficiently promoted nascent HDL formation. These results highlight that these cellular processes are interconnected through adiponectin and ABCA1- and ABCG1-dependent. In this pathway, adiponectin increased the affinity of apoA-I to cholesterol and effectively accelerated cholesterol removal from the plasma membrane to HDL particles. Thus, by accelerating HDL biogenesis, adiponectin may have therapeutic potential for atherosclerotic cardiovascular disease prevention and management.
•Adiponectin promotes efficiently apoA-I/HDL-mediated cholesterol efflux via ABCA1.•Adiponectin/apoA-I are associated with increased HDL size and lipid content.•Adiponectin accelerated cholesterol removal from plasma membrane to nascent HDL.•Accelerating HDL biogenesis by adiponectin may have therapeutic potential for CVD.
Physical activity has been shown to be beneficial for the prevention and management of hypertension. In the general population, physical activity has been shown to decrease mortality.
The purpose of ...this systematic review was to identify and synthesize the literature examining the impact of physical activity on mortality in patients with high blood pressure (BP).
An extensive search was conducted by two independent authors using Medline, Embase and Cochrane Library electronic databases (between 1985 and January 2012) and manual search from the reference list of relevant articles. Inclusion criteria were as follows: longitudinal design with minimum 1-year follow-up; hypertensive status of the cohort was indicated; and BP, physical activity, and mortality were measured.
Six articles evaluating a combined total of 48 ,448 men and 47 ,625 women satisfied the inclusion criteria. Cardiovascular and/or all-cause mortality were shown to be inversely related to physical activity in all studies. For example, patients with high BP who participated in any level of physical activity had a reduced risk (by 16-67%) of cardiovascular mortality, whereas a greater than two-fold increase in risk of mortality was noted in nonactive individuals. However, activity classification and parameters, such as frequency, duration, intensity, and volume, as well as BP status, were not consistent across studies.
Regular physical activity is beneficial for reducing mortality in patients with high BP. More research is needed to establish the impact of specific kinds of physical activity and whether any differences exist between sexes.
Estrogens and androgens are important regulators of sexual development and physiological processes in men and women, acting on numerous organs throughout the body. Moreover, they can contribute to a ...variety of pathologies, including osteoporosis, cancer, and cardiovascular and neurologic diseases. Analysis of estrogens and androgens in biological samples has been commonly performed using immunoassays for many years. However, these assays are suboptimal, as there is cross-reactivity with similar analytes, and they have moderate specificity and sensitivity. Thus, there is a clinical need to develop highly sensitive and specific methods for the accurate measurement of estrogen and androgen concentrations. Herein, we describe the development of three liquid chromatography coupled tandem mass spectrometry-based methods that incorporate the use of a Triple Quadrupole Mass Spectrometer for quantitative measurement of endogenous concentrations of various steroid hormones in human serum samples: (1) the simultaneous measurement of testosterone, androstenedione, and cortisol, (2) dehydroepiandrosterone (DHEA), and (3) 17β-estradiol (E
). The use of derivatizing reagents, Girard's reagent P and dansyl chloride, allowed for significant gains in sensitivity in the analysis of DHEA and E2, respectively, relative to the underivatized analyte. These procedures proved efficient and adequately sensitive for steroid hormone analysis in extracted patient sera samples from older men and postmenopausal women, providing reliable data down to low nanogram/ml and sub-nanogram/ml levels. Moreover, utilizing the combination of highly specific mass transitions associated with these analytes and their respective internal deuterated standards provided a high degree of specificity to the identity of these hormones.
