Stage Of Endothelial Dysfunction Research Articles

Четыре вида деструктивного влияния конфаундинг-эффектов кардиоренального континуума

Introduction. Studying the influence of risk factors (RF) for cardiovascular diseases (CVD) is a promising direction, since reducing their degree of influence can lead to an increase in overall life expectancy. The least studied of the RFs are confounders. Aim. To find out the influence of confounders in the chain of events of the cardiorenal continuum (CRC) using the example of a group of initially healthy 7,959 male workers of locomotive crews of the Trans-Baikal Railway aged 18-66 years. Materials and methods. Using 22 items of clinical and anamnestic data of a 6-year follow-up of a natural professional population of 7,959 men, multivariate statistical analysis was used to determine predictors of microalbuminuria (MAU), creatininemia (CR), reduced glomerular filtration rate (GFR), retinopathy (RP) and sudden cardiac death (SCD), which made it possible to construct a CRC from the prepared symptomatic blocks applying the synthesis method. The Cox proportional hazard model was used to determine the influence of all predictors of these symptoms on the increased risk of consecutive CRC events. The time of formation of MAU, RP, CR, reduced GFR, SCD, and the stages of endothelial dysfunction was found out using Kaplan-Meier (K-M) curves. The effects of damage to the endothelium by RFs, including confounders, were assessed by «failures» in K-M models. Results. Depending on the place of implementation in the CRC vascular bed, confounders manifest themselves by synergistic/additive and stabilizing processes caused by them in the endothelium. 1. They increase the risk of cardiovascular disease (CVD) / target organ damage (TOD) and the number of «failures» of the outcome being studied; 2. They increase the risk of CVD/TOD, but do not affect the number of «failures» of the outcome being studied; 3. They do not affect the increase in the risk of CVD/TOD, but increase the number of «failures» of the studied outcome; 4. They are associated with CVD/TOD, but do not affect the increase in risk and increase in the number of «failures» of the outcome being studied. Conclusion. Confounders of the CRC have four types of destructive effects. It is necessary to conduct targeted biochemical and morphological studies in order to finally clarify the processes of damage in the endothelium caused by risk factors and confounders and to resist their influence before the irreversible changes occur in the endothelial cell.

Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis.

Atherosclerosis is an immuno-metabolic disease involving chronic inflammation, oxidative stress, epigenetics, and metabolic dysfunction. There is compelling evidence suggesting numerous modifications including the change of the size, density, and biochemical properties in the low-density lipoprotein (LDL) within the vascular wall. These modifications of LDL, in addition to LDL transcytosis and retention, contribute to the initiation, development and clinical consequences of atherosclerosis. Among different atherogenic modifications of LDL, oxidation represents a primary modification. A series of pathophysiological changes caused by oxidized LDL (oxLDL) enhance the formation of foam cells and atherosclerotic plaques. OxLDL also promotes the development of fatty streaks and atherogenesis through induction of endothelial dysfunction, formation of foam cells, monocyte chemotaxis, proliferation and migration of SMCs, and platelet activation, which culminate in plaque instability and ultimately rupture. This article provides a concise review of the formation of oxLDL, enzymes mediating LDL oxidation, and the receptors and pro-atherogenic signaling pathways of oxLDL in vascular cells. The review also explores how oxLDL functions in different stages of endothelial dysfunction and atherosclerosis. Future targeted pathways and therapies aiming at reducing LDL oxidation and/or lowering oxLDL levels and oxLDL-mediated pro-inflammatory responses are also discussed.

The Inflammation Network in the Pathogenesis of Erectile Dysfunction: Attractive Potential Therapeutic Targets.

Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.

Placentation abnormalities in the pathophysiology of preeclampsia

Preeclampsia, a pregnancy-specific syndrome of hypertension and proteinuria, is one of the leading causes of perinatal morbidity and mortality. Although the initiating factor is unknown, a clearer picture regarding the network mechanisms of preeclampsia has begun to emerge during the past few years. The pathogenesis of preeclampsia can be described as having two stages. The first stage of preeclampsia involves abnormal placental implantation, followed by transition to the second stage of endothelial dysfunction. The link bridging these two stages is considered to be oxidative stress and disrupting angiogenesis. Discovery of the fundamental molecular mechanisms causing preeclampsia may provide a potential for prophylactic intervention and symptom amelioration. In this article, the clinical syndrome and risk factors of preeclampsia will be introduced, followed by the recent advances in our understanding of the pathophysiology of preeclampsia and, finally, research into aberrant placentation will be discussed.

Diabetic Retinopathy and Neuropathy

This is the seventh in a series of articles on presentations at the American Diabetes Association Annual Meeting, Orlando, Florida, 4–8 June 2004. Holger Gerhardt (Goteborg, Sweden) discussed pericytes and vascular stability in the diabetic retina, noting that these cells cover most of the endothelium and are present during the development of normal new blood vessels, while proliferative retinopathy classically shows “pericyte drop out” as an early pathological marker. It has been hypothesized that endothelial dysfunction leads to capillary occlusion and regression, causing ischemia, to which neovascularization with subsequent proliferative retinopathy is a response. In this schema, pericyte drop out may occur either before or after the stage of endothelial dysfunction. A number of markers can be used for characterizing pericytes. Mice that do not express platelet-derived growth factor (PDGF)-β have severe diffuse bleeding and die early in the neonatal period. There is diffuse pericyte loss in these mice, suggesting PDGF-β to be an important growth factor for the cells. An endothelium-specific PDGF-β knockout displays a variety of phenotypes with variable degrees of pericyte loss, with areas of pericyte-covered vessels and areas lacking pericytes and with severe retinopathy localized to the areas lacking pericytes. Gerhardt suggested that pericyte drop out is therefore sufficient to cause capillary occlusion and regression, leading to retinal ischemia. Why, though, he asked, is there a proliferative response rather than normal development of well-behaved new vessels repairing the region of ischemia, and how does retinal normal vascular development differ from that seen in neovascularization? The normal advancing vascular sprout extends “tip cells,” which appear to guide the development of the vasculature, following paths produced by astrocytes, which produce vascular endothelial growth factor (VEGF)-α in areas of hypoxia, with astrocyte VEGF-α downregulated after it becomes covered by new vessels. In the developing retina, the VEGF receptor (R)2 …

Vascular dysfunction and heart failure: Epiphenomenon or etiologic agent?

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)–induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response. (Am Heart J 2002;143:383-90.)

XANTHINE OXIDASE ACTIVATION IN MILD GESTATIONAL HYPERTENSION

Objective: We hypothesized that activation of the xanthine oxidase (XO) enzyme system is a potential source of free radicals in pregnancy-induced hypertension (PIH). Methods: A prospective observational study was carried out on 16 pregnant women who met the criteria of gestational hypertension [rise in blood pressure (BP) of 30 mm Hg systolic or 15 mm Hg diastolic after 20 weeks gestation or BP>140/90 mm Hg if earlier pressure is unknown] without proteinuria or any signs of renal impairment. Fourteen women with a clinically normal pregnancy matched for maternal age, parity, and gestational age acted as pregnant controls. Nonpregnant control women were members of the laboratory staff (n=15). Main Outcome Measures: Concentrations of free sulfhydryl (SH) groups, purine catabolites, lipid peroxidation products in plasma, and blood carboxyhemoglobin levels were used to follow oxidative stress and potential hemolysis. A noninvasive measurement of functional XO activity was carried out (i.e., the urinary ratio of the two metabolites of caffeine was estimated). Results: A pronounced oxidative stress was demonstrated in plasma samples of patients with hypertension by the elevated concentrations of uric acid and lipid peroxidation products. A reduced level of free sulfhydryl groups and an increased concentration of hypoxanthine (HX) were shown in normotensive pregnant individuals. The XO activity index was substantially higher in overweight pregnant subjects with mild hypertension [0.849±0.096 (p<0.01)] than in normotensive pregnant women or in age-matched nonpregnant subjects [0.596±0.105, 0.542±0.049 (means±SD), respectively]. Conclusions: Our study of mildly hypertensive pregnant subjects provides additional evidence of the putative role of XO activation as a source of free radicals in the early stage of endothelial dysfunction.