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Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes.
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PMID:Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. 1894 83

Obstructive sleep apnea (OSA) affects 25% of the Western adult population. It is an independent but seldom-recognized risk factor for hypertension, myocardial infarction, stroke, and increased mortality. Patients with OSA experience repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing that promote systemic oxidative stress and inflammation. Vascular endothelial inflammation and enhanced oxidative stress that are reversible with therapy for OSA were recently demonstrated directly in patients with OSA who were free of overt cardiovascular conditions. Vascular endothelial inflammation and enhanced oxidative stress may in part explain the accelerated progression of atherosclerosis in patients with untreated OSA. The present review will focus on indirect and direct evidence of vascular endothelial inflammation and enhanced oxidative stress in patients with OSA. The potential utility of venous endothelial biopsy technique in evaluating the mechanisms that mediate the effects of systemic conditions such as diabetes mellitus, sleep apnea, and obesity on the vascular endothelium will also be discussed.
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PMID:Inflammation, oxidative stress, and the vascular endothelium in obstructive sleep apnea. 1923 54

Evidence suggests that insulin delivery to skeletal muscle interstitium is the rate-limiting step in insulin-stimulated muscle glucose uptake and that this process is impaired by insulin resistance. In this review we examine the basis for the hypothesis that insulin acts on the vasculature at three discrete steps to enhance its own delivery to muscle: (1) relaxation of resistance vessels to increase total blood flow; (2) relaxation of pre-capillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular recruitment); and (3) the trans-endothelial transport (TET) of insulin. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. However, there is controversy as to whether this occurs at physiological concentrations of, and exposure times to, insulin. The microvasculature is recruited more quickly and at lower insulin concentrations than are needed to increase total blood flow, a finding consistent with a physiological role for insulin in muscle insulin delivery. Microvascular recruitment is impaired by obesity, diabetes and nitric oxide synthase inhibitors. Insulin TET is a third potential site for regulating insulin delivery. This is underscored by the consistent finding that steady-state insulin concentrations in plasma are approximately twice those in muscle interstitium. Recent in vivo and in vitro findings suggest that insulin traverses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET. Thus, muscle insulin delivery, which is rate-limiting for its metabolic action, is itself regulated by insulin at multiple steps. These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation.
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PMID:The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. 1928 61

Cardiovascular disease remains the leading cause of death and disability in industrialized nations. The risk of cardiovascular disease is significantly reduced by lifestyle choices that promote cardiovascular health. Epidemiological data demonstrate that poor dietary choices, lack of exercise, smoking, obesity, stress, and pollution all increase cardiovascular risk. Poor habits and choices also have been shown to have adverse effects on vascular endothelial homeostasis leading to the development of endothelial dysfunction. Endothelial dysfunction includes broad regulatory changes leading to the expression of a vasoconstrictive, pro-thrombotic, and pro-inflammatory phenotype of the vascular endothelium. Interest in assessing lifestyle interventions as they relate to endothelial function has been encouraged by data demonstrating that measurements of endothelial function in easily accessible vascular beds such as the brachial artery correlate with risk for future cardiovascular events. Given the logistical difficulties and costs of performing large scale clinical trials assessing the ability of many lifestyle interventions designed to reduce cardiovascular risk, employing measures of endothelial function as a surrogate outcome for cardiovascular risk has allowed researchers to determine the biological plausibility of epidemiological data in this area with smaller studies. Newer study techniques, including genomic methodologies, now allow for better delineation of the mechanisms by which lifestyle choices affect the vascular endothelium and of the role of genetic variation in modifying these effects. This review discusses the effects of lifestyle choices on vascular endothelial function, the role and relevance of using studies that assess endothelial function in assessing cardiovascular risk, and future research directions in this area.
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PMID:Lifestyle choices and endothelial function: risk and relevance. 1935 4

Obesity is associated with numerous co-morbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension and others. As obesity is considered to be a major risk factor for atherosclerosis, understanding of the underlying mechanisms leading to obesity and linking obesity with atherogenesis is necessary, for the development of therapeutic strategies against atherosclerosis. The pathophysiology of CVD linked to obesity is an area of intensive research. In this review we examine the role of obesity on CVD, and we focus on specific mechanisms of major importance in atherogenesis, such as the role of adipokines, insulin resistance, endothelial function and cardiac structure with emphasis on the effects of obesity on vascular endothelium and atherosclerosis. We then proceed from the pathophysiology of obesity to clinical practice, and we discuss clinical studies linking obesity with subclinical or overt CVD. We highlight that obesity is an easily assessed cardiovascular risk factor in the clinical setting and strategies to promote optimal body weight should be encouraged.
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PMID:Obesity and cardiovascular disease: from pathophysiology to risk stratification. 1939 37

Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in white adipose tissue (WAT). The vascular endothelium plays an interactive role in these infiltration and inflammatory processes. Mature and hypertrophic adipocytes are considered as the major adipogenic cell type secreting proinflammatory cytokines in WAT. In contrast, the proinflammatory capacity of preadipocytes and their role in endothelial cell activation have been neglected so far. To gain new insights into this molecular and cellular cross-talk, we examined the proinflammatory expression and secretion of normoxia, hypoxia, and TNFalpha-treated human preadipocytes and adipocytes (SGBS cells) and their impact on human microvascular endothelial cell (HMEC-1) function. In this study, stimulation of HMEC-1 with conditioned media (CM) from preadipocytes increased endothelial ICAM-1 expression and monocyte adhesion but not adipocyte-CM. After hypoxia and TNFalpha stimulation of SGBS cells, adipocyte-CM induced and preadipocyte-CM enhanced the monocyte adhesion. Concordantly, the expression of proinflammatory adipokines was considerably higher in preadipocytes than in adipocytes. SGBS-CM upregulated the phosphorylation of three MAPK pathways, STAT1/3, and c-Jun in HMEC-1, whereas the NF-kappaB pathway was not affected. Inhibitor experiments showed that monocyte/endothelial cell-cell adhesion and endothelial ICAM-1 expression was JNK and JAK-1/STAT1/3 pathway dependent and revealed IL-6 as a major mediator in CM increasing monocyte/endothelial cell-cell adhesion via the STAT1/3 pathway. Our study shows that preadipocytes rather than adipocytes operate as potent activators of endothelial cells. This can be enhanced in preadipocytes and induced in adipocytes by TNFalpha and hypoxia in a manner similar to what may occur in WAT in the etiology of obesity.
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PMID:Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNFalpha exposure. 1954 91

Cardiovascular diseases (CVD) are the leading cause of mortality in Croatia and in Europe. Primary prevention of CVD involves intervention before the onset of disease, and prevention of modifiable risk factors, i.e. cigarette smoking, hyperlipidemia, arterial hypertension, diabetes mellitus, inactivity, obesity. These risk factors are strongly associated and lead to impaired vascular endothelial function, chronic injury of endothelium, platelet activation and aggregation, atherosclerotic plaque formation, and in the end manifestation of CVD. The risk of any coronary event increases exponentially when two or more risk factors are present. Aside from conventional factors, it has been demonstrated that raised levels of C-reactive protein (CRP), cytokines, homocysteine and fibrinogen are also important promotors of the disease, pointing to partially inflammatory nature of coronary atherosclerosis. The effects of risk factors such as smoking, arterial hypertension and hyperlipidemia on vascular endothelium are proven to be reversible. According to Guidelines on Cardiovascular Disease Prevention in Clinical Practice of the European Society of Cardiology (2007), population is advised to follow the formula 0 3 5 140 5 3 0. It suggests that crucial measures in preserving cardiovascular health are as follows: no smoking (0), walking 3 km daily or 30 minutes of any moderate activity (3), blood pressure less than 140 mm Hg systolic (140), total blood cholesterol less than 5 mmol/L (5), LDL cholesterol less than 3 mmol/L (3), avoidance of overweight and diabetes (0). There are many studies proving the beneficial effects of statins and ACE inhibitors in improving endothelial function and endorsing primary prevention.
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PMID:[Primary prevention of cardiovascular disease]. 1968 67

In recent years, an explosion of research related to the cellular and vascular accompaniments of the metabolic syndrome has generated intense interest and controversy. Attention has focused on the vascular endothelium, where heightened, low-grade inflammatory processes lead to a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis. Inflammatory biocytokines, such as C-reactive protein, have been speculated to be both markers and mediators of oxidative stress and endovascular toxicity. Adipocytokines originating from fatty tissue have reinforced the concept that fat is a metabolically active organ rather than inert tissue. To fully elucidate its complex pathogenetic mechanisms, further inquiry into the inflammatory components of the metabolic syndrome is warranted. Unraveling the role of emerging proinflammatory markers has the promising potential to shed light into the underlying pathophysiology of the epidemic of obesity and the metabolic syndrome and thus help devise effective therapies.
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PMID:Cytokine biomarkers, endothelial inflammation, and atherosclerosis in the metabolic syndrome: emerging concepts. 1972 72

The process of aging is accompanied by several modifications in the hemostatic system at different levels (blood coagulation, fibrinolysis, platelet activity, vascular endothelium). These changes may explain the higher incidence of arterial and venous thrombosis in the elderly compared to young people. Genetic and environmental factors modulate in different combinations the expression of proteins involved in the hemostatic process. Among the latter, diet and smoking habits play an important role, as well as physical exercise and, for women, hormonal status. A gradual and progressive development of a low-grade inflammatory state (clearly demonstrated in the elderly) is also an important factor that influences hemostasis during aging. In spite of the fact that the increased hypercoagulable state observed with aging may account for the higher incidence of thrombosis in the elderly, the finding of a similar pattern of coagulation activation in healthy centenarians suggests that a hypercoagulable state is compatible with health and longevity. Taking also into consideration that no laboratory parameters of hemostasis are predictive of thrombosis on an individual basis, a physician's behavior towards aging patients (e.g. prescription of hormonal replacement therapy to a woman during menopause) should not be affected by laboratory tests, but mainly by a patient's clinical history and the presence of strong risk factors for thrombosis other than age (e.g. diabetes mellitus, arterial hypertension, dyslipidemia, obesity, smoking).
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PMID:The hemostatic system through aging and menopause. 1981 Dec 41

Adipose tissue is an endocrine organ secreting more than 30 various adipokines which regulate wide spectrum of metabolic and immune processes. Obesity is associated with development of adipose tissue inflammation. This inflammation is characterized by infiltration with macrophages, alterations of adipokine secretion, development of insulin resistance. All these factors promote atherosclerosis. Inflammation of perivascular adipose tissue is especially important. Adipokines damage vascular endothelium via paracrine pathway. Cytokines released by macrophages as well as changes of adipokine secretion lead to endothelial dysfunction - the first stage of atherogenesis. Besides specific action curative factors used in obesity, metabolic syndrome, and diabetes mellitus also produce anti-inflammatory effect and thus diminish risk factors of cardiovascular diseases, rate of their development, and alleviate manifestations of atherosclerosis. Inflammation of adipose tissue is a connecting link between obesity and atherosclerosis. This review contains an outline of roles of various major adipokines in development of atherosclerosis as well as synopsis of anti-inflammatory and antiatherogenic effects of glytazones , metformin, rimonabant, statins, and of lowering of body weight.
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PMID:[Adipose tissue inflammation and atherosclerosis]. 2003 88


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