Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease

PURPOSE OF REVIEW: Adiponectin is secreted exclusively by adipocytes, aggregates in multimeric forms, and circulates at high concentrations in blood. This review summarizes recent studies highlighting cellular effects of adiponectin and its role in human lipid metabolism and atherosclerosis. RECENT FINDINGS: Adiponectin is an important autocrine/paracrine factor in adipose tissue that modulates differentiation of preadipocytes and favors formation of mature adipocytes. It also functions as an endocrine factor, influencing whole-body metabolism via effects on target organs. Adiponectin multimers exert differential biologic effects, with the high-molecular-weight multimer associated with favorable metabolic effects (i.e. greater insulin sensitivity, reduced visceral adipose mass, reduced plasma triglycerides, and increased HDL-cholesterol). Adiponectin influences plasma lipoprotein levels by altering the levels and activity of key enzymes (lipoprotein lipase and hepatic lipase) responsible for the catabolism of triglyceride-rich lipoproteins and HDL. It thus influences atherosclerosis by affecting the balance of atherogenic and antiatherogenic lipoproteins in plasma, and by modulating cellular processes involved in foam cell formation. SUMMARY: Recent studies emphasize the role played by adiponectin in the homeostasis of adipose tissue and in the pathogenesis of the metabolic syndrome, type 2 diabetes, and atherosclerosis. These pleiotropic effects make it an attractive therapeutic target for obesity-related conditions.     

Molecular mechanisms mediating pathological plasticity in Huntington's disease and Alzheimer's disease

Neurodegenerative diseases such as Huntington's disease and Alzheimer's disease, although very different in etiology, share common degenerative processes. These include neuronal dysfunction, decreased neural connectivity, and disruption of cellular plasticity. Understanding the molecular mechanisms underlying the neural plasticity deficits in these devastating conditions may lead the way toward new therapeutic targets, both disease-specific and more generalized, which can ameliorate degenerative cognitive deficits. Furthermore, investigations of 'pathological plasticity' in these diseases lend insight into normal brain function. This review will present evidence for altered plasticity in Huntington's and Alzheimer's diseases, relate these findings to symptomatology, and review possible causes and commonalities.     

Why sex matters: the biological mechanisms of cardiovascular disease

Cardiovascular disease (CVD) is the leading determinant of mortality and morbidity in women. However, a full understanding of the basic and clinical aspects of CVD in women is far from being accomplished. Sexual dimorphism in CVD has been reported both in humans and experimental animals. Menopause is a risk factor for CVD due to the reduction of endogenous estrogen, although the mechanisms underlying are poorly understood. Estrogens act through binding to vascular estrogen receptors and by non-genomic mechanisms. Advances in this field are essential to improve CVD diagnostic and clinical strategies in women, and to develop sex-specific prevention plans as much as female-oriented treatment algorithms. This paper reviews pathophysiology of CVD in women and its potential clinical implications. Particular emphasis is given to biochemical markers and to indicators of cardiovascular dysfunction and damage. Estimation of these parameters, central to cardiovascular pathophysiology, could represent a particularly relevant tool in female patients. More research is needed to identify women who will profit most of early intervention.     

The antioxidant hypothesis of cardiovascular disease: epidemiology and mechanisms

Plasma levels of major essential antioxidants were determined in representative random samples of middle-aged men from 16 European study populations which differed up to 6-fold in age-specific mortality from ischaemic heart disease (IHD). In 12 study populations having total plasma cholesterol in the medium range (5.7-6.2 mmol/l) and usual blood pressure, both these classical risk factors lacked a significant correlation to IHD mortality, whereas the absolute level of vitamin E (alpha-tocopherol) showed a strong inverse correlation (r2 = 0.63, P = 0.002). On evaluation of all study populations, cholesterol and diastolic blood pressure had a moderate direct association with IHD, but their importance still remained inferior to that of vitamin E as an inversely associated, presumably protective factor. In stepwise regression and multiple regression analysis, the IHD mortality of the study populations was predictable to 62% by lipid-standardized vitamin E, to 79% by vitamin E and total cholesterol, to 83% after inclusion of lipid-standardized vitamin A (retinol) and to 87% by all the above parameters plus diastolic blood pressure. In conclusion, in the present study the plasma status of vitamin E is the most important factor to explain cross-cultural differences of IHD mortality. This finding is consistent with the hypothesis of the prevention of arteriosclerosis by antioxidant protection against peroxidative lipoprotein modification, but does not exclude additional effects of antioxidant vitamins, e.g. on the cellular or immunological level.     

Adipokines in inflammation and metabolic disease

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.     

Clonal hematopoiesis: Genes and underlying mechanisms in cardiovascular disease development

The clonal hematopoiesis when occurring without hematologic abnormalities is defined as clonal hematopoiesis of indeterminate potential (CHIP). Aging causes accumulation of somatic mutations, and hematopoietic stem cells (HSCs) can develop clonal expansion of different lineages by these mutations. CHIP has a correlation with cancer and cardiovascular disease (CVD) through acquired mutations in genes. DNMT3A, TET2, ASXL1, and JAK2 genes as well as other genes are the most common somatic mutations causing CHIP and CVD in an older age. Other factors such as cholesterol level, laboratory tests and indexes also affect CVD. In addition, mutations in adenosine triphosphate–binding cassette transporters and also chronic stress in nervous system can result in HSCs proliferation and CVD. However, laboratory tests and indexes are not sensitive for CVD diagnosis. But the therapeutic interventions can be helpful to prevent CVD cases by targeting somatic mutations, chemokine receptors, and growth factors in HSCs. Also, new drugs can control CVD by targeting of cells and their signaling pathways in HSCs. Therefore, more investigations are needed and more questions should be answered for the relationship between CHIP and CVD as a challenging issue in future.     

Epigenetic mechanisms in health and disease: BCEC 2017

The Barcelona Conference on Epigenetics and Cancer (BCEC) entitled “Epigenetic Mechanisms in Health and Disease” was held in Barcelona, October 26-26, 2017. The 2017 BCEC was the fifth and last edition of a series of annual conferences organized as a joint effort of five leading Barcelona research institutes together with B-Debate. This edition was organized by Albert Jordan from the Molecular Biology Institute of Barcelona (IBMB-CSIC) and Marcus Bushbeck from the Josep Carreras Leukaemia Research Institute (IJC). Jordi Bernués, Marian Martínez-Balbás, and Ferran Azorín were also part of the scientific committee. In 22 talks and 51 posters, researchers presented their latest results in the fields of histone variants, epigenetic regulation, and chromatin 3D organization to an audience of around 250 participants from 16 countries. This year, a broad number of talks focused on the epigenetic causes and possible related treatments of complex diseases such as cancer. Participants at the 2017 BCEC elegantly closed the series, discussing progress made in the field of epigenetics and highlighting its role in human health and disease.     

Sleep mechanisms in health and disease

Excess sleepiness, abnormal sleep patterns, non-restorative sleep, and fatigue are becoming increasingly pervasive in modern society. Identifying substances and mechanisms that modulate sleep and vigilance during health and disease is a critical prelude to eventual development of interventions to prevent or alleviate these disabling problems. A unified interdisciplinary approach that includes neurophysiology, neuroanatomy, neurochemistry, and molecular biology will promote elucidation of the complex biology of sleep. Integration of basic sleep physiology with modern genetic techniques will eventually lead to identification of specific genes and substances involved in regulation of various facets of sleep. The review presented here highlights recent progress in defining the anatomy and physiology of sleep-wake regulatory systems, delineating the role of homeostatic and circadian process in regulating sleep and wakefulness, and establishing the relationship of sleep and sleep disorders to other medical conditions. Particular emphasis is placed on reviewing the interactions between sleep, infectious challenge, and host defense response, and on identifying mechanisms that contribute to variation in sleep patterns among various strains of inbred mice.     

Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project

Existing evidence on the relationship between cardiovascular health(CVH) metrics and cardiovascular disease(CVD) was primarily derived from western populations. We aimed to evaluate the benefits of ideal CVH metrics on preventing incident atherosclerotic CVD(ASCVD) in Chinese population. This study was conducted among 93,987 adults from the China-PAR project(Prediction for ASCVD Risk in China) who were followed up until 2015. Cox proportional hazard regression models were used to estimate the hazard ratios(HRs) and their corresponding 95% confidence intervals(CIs) of CVH metrics for the risk of ASCVD, including coronary heart disease(CHD), stroke and ASCVD death. We further estimated the population-attributable risk percentage(PAR%) of these metrics in relation to each outcome. We observed gradient inverse associations between the number of ideal CVH metrics and ASCVD incidence. Compared with participants having ≤2 ideal CVH metrics, the multivariable-adjusted HRs(95% CIs) of ASCVD for those with 3, 4, 5, 6 and 7 ideal CVH metrics were 0.83(0.74–0.93), 0.66(0.59–0.74), 0.55(0.48–0.61), 0.44(0.38–0.50) and 0.24(0.18–0.31), respectively(P for trend 0.0001). Approximately 62.1% of total ASCVD, 38.7% of CHD, 66.4% of stroke, and 60.5% of ASCVD death were attributable to not achieving all the seven ideal CVH metrics. After adjusting effects of ideal health factors, having four ideal health behaviors could independently bring adults health benefits in preventing 17.4% of ASCVD, 18.0% of CHD, 16.7% of stroke, and 10.1% of ASCVD death. Among all the seven CVH metrics, to keep with ideal blood pressure(BP) implied the largest public health gains against various ASCVD events(PAR% between 33.0% and 47.2%), while ideal diet was the metric most difficult to be achieved in the long term. Our study indicates that the more ideal CVH metrics adults have, the less ASCVD burden there is in China. Special efforts of health education and behavior modification should be made on keeping ideal BP and dietary habits in general Chinese population to prevent the epidemic of ASCVD.     

Circular RNA in cardiovascular disease: Expression,mechanisms and clinical prospects

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non-coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.     

Relaxin and the extracellular matrix: molecular mechanisms of action and implications for cardiovascular disease

Myocardial fibrosis is a common endpoint in a variety of cardiac pathologies. It results from excessive accumulation of collagen and other materials that together comprise the extracellular matrix (ECM). In the past decade, the peptide hormone relaxin has emerged as an important regulator of the ECM within several organs, including the heart, and has been suggested as a novel therapeutic agent for the treatment of fibrotic disorders. This review summarises research on the anti-fibrotic actions of relaxin, outlines the potential mechanisms by which relaxin regulates the ECM in cardiovascular tissues and examines the implications of this research for the management of heart disease. Some of the contradictions in the literature are also addressed in order to clarify the role of relaxin as an anti-fibrotic factor in vivo.     

Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and it is well known that end-stage renal disease (ESRD) is a profound consequence of the progression of CVD. Present treatments only slow CVD progression to ESRD, and it is imperative that new therapeutic strategies are developed to prevent the incidence of ESRD. Because epoxyeicosatrienoic acids (EETs) have been shown to elicit reno-protective effects in hypertensive animal models, the current review will focus on addressing the reno-protective mechanisms of EETs in CVD. The cytochrome P-450 epoxygenase catalyzes the oxidation of arachidonic acid to EETs. EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs) with vasodilatory, anti-inflammatory, antihypertensive, and antiplatelet aggregation properties. EETs also have profound effects on vascular migration and proliferation and promote angiogenesis. The progression of CVD has been linked to decreased EETs levels, leading to the concept that EETs should be therapeutically targeted to prevent end-organ damage associated with CVD. However, EETs are quickly degraded by the enzyme soluble epoxide hydrolase (sEH) to their less active diols, dihydroxyeicosatrienoic acids (DHETs). As such, one way to increase EETs level is to inhibit their degradation to DHETs by using sEH inhibitors. Inhibition of sEH has been shown to effectively reduce blood pressure and organ damage in experimental models of CVD. Another approach to target EETs is to develop EET analogs with improved solubility and resistance to auto-oxidation and metabolism by sEH. For example, stable ether EET analogs dilate afferent arterioles and lower blood pressure in hypertensive rodent animal models. EET agonists also improve insulin signaling and vascular function in animal models of metabolic syndrome.     

The endoplasmic reticulum in cardiovascular health and disease

The endoplasmic reticulum has an intricate network of pathways built to deal with the secretory and integral membrane protein synthesis demands of the cell, as well as adaptive responses set up for the endoplasmic reticulum to rely on when stressed. These pathways are both essential and complex, and because of these 2 factors, several situations can lead to a dysfunctional endoplasmic reticulum and result in a dysfunctional cell with the potential to contribute to the progression of disease. The endoplasmic reticulum has been implicated in several metabolic, neurodegenerative, inflammatory, autoimmune, and renal diseases and disorders, and in particular, cardiovascular diseases. The role of the endoplasmic reticulum in cardiovascular disease shows how the change in function of a particular microscopic organelle can lead to macroscopic changes in the form of disease.     

Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling

Cannabinoids include not only plant-derived compounds (of which delta9-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis), but also synthetic agents and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol. Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB1 and CB2. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB1 receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB1 receptor. Both cannabinoid receptors are primarily coupled to Gi/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB1 receptors also modulates the activity of K+ and Ca2+ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on apoptosis. CB, receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling. Cannabinoid actions on the cardiovascular system have been widely interpreted as being mediated by CB1 receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist. Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to Gi/o protein signalling. Anandamide also activates vanilloid VR1 receptors on sensory nerves and releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors. Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction. Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.     

Shear-mediated platelet activation in the free flow: Perspectives on the emerging spectrum of cell mechanobiological mechanisms mediating cardiovascular implant thrombosis

Shear-mediated platelet activation (SMPA) is central in thrombosis of implantable cardiovascular therapeutic devices. Despite the morbidity and mortality associated with thrombosis of these devices, our understanding of mechanisms operative in SMPA, particularly in free flowing blood, remains limited. Herein we present and discuss a range of emerging mechanisms for consideration for “free flow” activation under supraphysiologic shear. Further definition and manipulation of these mechanisms will afford opportunities for novel pharmacologic and mechanical strategies to limit SMPA and enhance overall implant device safety.     

Glycosylation in cellular mechanisms of health and disease

Glycosylation produces an abundant, diverse, and highly regulated repertoire of cellular glycans that are frequently attached to proteins and lipids. The past decade of research on glycan function has revealed that the enzymes responsible for glycosylation-the glycosyltransferases and glycosidases-are essential in the development and physiology of living organisms. Glycans participate in many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. This review discusses the increasingly sophisticated molecular mechanisms being discovered by which mammalian glycosylation governs physiology and contributes to disease.