Barbatic acid inhibits inflammatory responses and endothelial dysfunction in hypertension by regulating HIF1A/FLT1 pathway: A computer-aided biolabel research and experimental validation.

Oxidative stress, the capo of endothelial dysfunction in chronic renovascular hypertension

NLRP3 inflammasome contributes to endothelial dysfunction in angiotensin II-induced hypertension in mice

Objective:Angiogenic T cells (Tang cells), a recently discovered T-cell subset, have been reported involved in the repair of endothelial injury. The purpose of this study was to explore the correlation of immunologic senescence and pro-inflammatory capacity of Tang cells with endothelial dysfunction in hypertensive patients.Methods:Immunological characteristics of Tang cells (CD3+CD31+CXCR4+) from hypertensive patients with or without endothelial dysfunction were elucidated by surface immunophenotyping and intracellular cytokine staining. Endothelial function was measured by flow-mediated dilation (FMD).Results:The frequency of CD28null subset in CD4+ Tang cells was notably elevated in hypertensive patients with endothelial dysfunction, which was negatively associated with FMD. The high frequency of CD28nullCD4+ Tang cells was an independent risk factor of endothelial dysfunction with good diagnostic performance in ROC curve analysis. Immunophenotyping revealed that this specific subset of Tang cells exhibited senescent profile and has low hTERT expression. CD28nullCD4+ Tang cells produced high levels of inflammatory cytokines, IL-6, IFN-γ and TNF-α, and significantly correlated with the systemic inflammation in hypertensive patients with endothelial dysfunction.Conclusion:Collectively, our findings demonstrate for the first time that CD28null subset in CD4+ Tang cells with senescent and pro-inflammatory phenotype is dependently correlated with impaired FMD and systemic inflammation, which might contribute to the immunopathologic mechanism of endothelial dysfunction. Identification of a pathogenic CD4+ Tang-cell subset lacking CD28 may offer opportunities for the evaluation and management of endothelial dysfunction in hypertension.

Targeting endothelial SMAD4 ameliorates endothelial dysfunction in hypertensive mice.

The aim of the study was to examine whether the circulating cell adhesion molecules, von Willebrand factor (vWf) and endothelin-1, are elevated in patients with essential hypertension with no other risk factors for atherosclerosis and thus may serve as a markers of endothelial dysfunction in uncomplicated hypertension. Furthermore, the effect of treatment with the ACE inhibitor, quinapril, on levels of endothelial dysfunction markers were studied. The levels of adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, P-selectin), von Willebrand factor (vWf) and endothelin-1 were measured in patients with hypertension without any other risk factors of atherosclerosis before and after treatment with quinapril (n = 22) and in normotensive controls (n = 22). Compared with normotensive subjects, the hypertensive patients had significantly higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf (119 vs 105 IU/dl, P < 0.05) and endothelin-1 (5.76 vs 5.14 fmol/ml, P < 0.05). Three-month treatment of hypertensive patients with quinapril led to a significant decrease in the levels of endothelin-1 (5.76 vs 5.28 fmol/ml, P < 0.01). We did not observe significant changes in the levels of adhesion molecules and vWf after ACE inhibitor treatment, although a trend toward a decrease was apparent with all these parameters. Patients with uncomplicated hypertension with no other risk factors of atherosclerosis had significantly elevated levels of ICAM-1, vWf, and endothelin-1. Our data suggest that these factors may serve as markers of endothelial damage even in uncomplicated hypertension. In hypertensive patients, treatment with the ACE inhibitor quinapril resulted in a significant decrease in endothelin-1 levels. These findings indicate a beneficial effect of ACE inhibitors on endothelial dysfunction in hypertensive patients.

In the past, endothelium was thought to be only a mechanical barrier. Today, endothelium is known to be a tissue regulating vascular tone, cell growth and the interaction between the leukocytes, thrombocytes and the vessel wall. It also synthesizes growth factors and thrombo-regulatory molecules and responds to physical and chemical signals. Even though the term "endothelial dysfunction" is generally used for deterioration of endothelium-dependent vasodilatation; the term also includes the abnormalities between endothelium and leukocytes, thrombocytes and regulatory molecules and conditions resulting in aberrant endothelium activation. Healthy endothelium is essential for cardiovascular control. Thus, it plays an important role in pathogenesis of many diseases and cardiovascular problems such as atherosclerosis, systemic and pulmonary hypertension, cardiomyopathies and vasculitides. The aim of this chapter is to explain endothelial dysfunction and the circulating molecules of endothelial cells as they become potential targets of therapeutic approach for hypertension. This chapter reviews the roles of endothelial dysfunction in hypertension by addressing (1) the nature of endothelial function, (2) mechanisms of endothelial dysfunction and its relationship with the diseases (3) also endothelial function testing (4) the role of endothelial dysfunction and hypertension and (4) the effects of antihypertensive therapeutic options on the endothelial dysfunction. In addition to these, the role of endothelial dysfunction in white coat hypertension has been discussed. The key connections between hypertension and endothelial dysfunction are vitally important for future studies to permit new interventions to be designed and released.

With a prevalence in excess of 20%, hypertension is a common finding among Western adult populations. Hypertension is directly implicated in the pathophysiology of various cardiovascular disease states and is a significant contributor to ill health, leading to an excess of both morbidity and mortality. The etiology of hypertension has been explored in depth, but the pathophysiology is multifactorial, complex, and poorly understood. Recent interest has been directed toward investigating the purported role of the endothelium, which acts as an important regulator of vascular homeostasis. Endothelial dysfunction is now recognized to occur in hypertension, regardless of whether the etiology is essential or secondary to endocrine or renal processes. Nitric oxide (NO) is a volatile gas produced by endothelial cells that acts to maintain vascular tone. Reduced bioavailability of NO appears to be the key process through which endothelial dysfunction is manifested in hypertension. The result is of an imbalance of counteracting mechanisms, normally designed to maintain vascular homeostasis, leading to vasoconstriction and impaired vascular function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress, possibly as a result of systemic and localized inflammatory responses. This article provides an overview of endothelial dysfunction in hypertension and focuses on the purported role of oxidative stress and inflammation as the catalysts for this process.

In the hypertensive circulation, endothelial cells may release less nitric oxide or more endothelin-1, both powerful vasoactive substances, suggesting an attractive hypothesis for the initiation or reinforcement of hypertension. These substances, however, are not the only way that endothelial dysfunction could be involved in hypertension. In this work we examine the role of the endothelium as a diffusion barrier to vasoconstrictor substances, as a metabolic barrier and as a secretory source of paracrine hormones. The evidence that endothelial cell dysfunction occurs in different forms of hypertension comes mainly from the loss of relaxation revealed by the 'acetylcholine test' in a variety of preparations. We examined the strength of this evidence in terms of the stability of the agonist, equilibrium between agonist and receptor, and variations in acetylcholine and other receptor populations on endothelial and smooth muscle cells. The range (Emax) and sensitivity (EC50) of the acetylcholine test was considered in a novel approach to determine the full range by in vitro assay. Using conscious rabbits, we showed that the vascular amplifier of resistance in the hypertensive bed can lead to misinterpretation of changes in reactivity. The question of endothelial dysfunction in hypertension as determined by the acetylcholine test is far from proven.

Hypertension is associated with endothelial dysfunction that is attributable to oxidative stress and a proinflammatory state. Under these conditions, enhanced expression of cyclooxygenase-2 might lead to increased production of vasoconstrictor prostanoids and reactive oxygen species that reduce the bioavailability of endothelium-derived nitric oxide. To investigate the contribution of cyclooxygenase-2 activity to endothelial dysfunction in human hypertension, we evaluated brachial artery vasodilator function by ultrasound in 29 hypertensive patients before and after treatment with the selective cyclooxygenase-2 inhibitor celecoxib or placebo in a randomized, double-blind study. Brachial artery flow-mediated dilation improved from a baseline of 7.9+/-4.5% to 9.9+/-5.1% (P=0.005) 3 hours after the first dose and to 10.1+/-6.1% (P=0.006) after 1 week of treatment with celecoxib. In contrast, placebo treatment had no significant effect on flow-mediated dilation (8.1+/-4.4%, 8.3+/-3.5%, and 8.0+/-3.2%, respectively). Neither treatment altered nitroglycerin-mediated dilation, extent of reactive hyperemia, or baseline arterial diameter. Celecoxib treatment had no significant effect on the urinary concentrations of F2 isoprostane or thromboxane metabolites. However, urinary concentrations of the prostacyclin metabolite 2,3-dinor-6-ketoprostglandin F1alpha were significantly lower after 1 week of celecoxib treatment. Thus, cyclooxygenase-2 products contribute to endothelial dysfunction in hypertension, and treatment with a cyclooxygenase-2 inhibitor could have a beneficial effect in this setting. However, cyclooxygenase-2 inhibition also has an adverse effect on prostacyclin production that could promote thrombosis, and the net clinical consequences of improved endothelial function versus loss of prostacyclin merits further investigation.

Coronary artery disease is the major cause of death worldwide. Hypertension is a major risk factor for developing coronary disease. It is now recognized that endothelial dysfunction is an early marker of coronary artery disease before structural changes to the vessel wall are apparent on angiography or intravascular ultrasound and that it has a prognostic value in predicting cardiovascular events in hypertensive patients. This review addresses recent developments in hypertension-induced endothelial dysfunction. Hyperaldosteronism causes endothelial dysfunction independent of high blood pressure. Exaggerated exercise blood pressure response has been related to endothelial dysfunction. Cyclosporin-A-induced endothelial dysfunction is related to reduced cholesterol content in caveolae. Chronic kidney disease induces changes in caveoli-1 and thus contributes to the reduced nitric oxide bioavailability, and causes oxidative stress independent of the high blood pressure. Asymmetric dimethylarginine plays a role in endothelial dysfunction in hypertensive patients independent of insulin resistance. 20-Hydroxyeicosatetraenoic acid is an independent predictor of hypertension in postmenopausal women. Endothelial dysfunction precedes and predicts the development of hypertension in postmenopausal women. Oral treatment with L-arginine improves endothelial dysfunction in hypertensives and lowers the blood pressure. The pathophysiology of endothelial dysfunction in hypertension is multifactorial. Recent findings have contributed to our understanding of mechanisms of endothelial dysfunction and support a role for early intervention to prevent irreversible vascular and organ damage.

In the last decade, significant advances have occurred in our understanding of the presence and nature of endothelial dysfunction in a number of cardiovascular conditions, including hypertension. Endothelium-derived nitric oxide (NO) is recognized as an important mediator of endothelium-dependent vascular relaxation, and a defect in the endothelium-derived NO system--possibly decreased synthesis and/or release of NO by endothelial cells--is now known to cause the abnormal response to acetylcholine in hypertensive vessels and to account at least in part for the increased vascular resistance observed in hypertension. Extensive research by our laboratory and others to determine the nature of the defect in the NO system has found that the defect is not related to decreased availability of L-arginine, the NO precursor, or to a defect at the muscarinic receptor level or a specific G protein-dependent intracellular signal-transduction pathway; nor is it related to extracellular inactivation of NO by superoxide anion. These findings have contributed to our understanding of endothelial dysfunction in essential hypertension and have pointed out distinctions between the mechanisms leading to this vascular abnormality in hypertensive and hypercholesterolemic patients. While the exact nature of the NO system defect in hypertension is still to be clarified, the vasoconstrictive and proatherogenic effects of endothelial dysfunction probably contribute to the cardiovascular complications associated with elevated blood pressure. Continued research targeted at the identification of the precise mechanism(s) responsible for endothelial dysfunction in hypertension may lead to the development of novel therapeutic strategies to reduce the vascular complications associated with the hypertensive process.

Pathological changes in the endothelium are the earliest determinants of endothelial dysfunction and atherosclerosis in hypertension (HT). The diagnostic and prognostic role of copeptin in various diseases is well-recognized. This study aims to investigate the relationship between serum copeptin levels and non-invasive endothelial function indicators determined by flow-mediated dilation (FMD) and pulse wave analysis (PWA) in dipper and non-dipper HT patients. In this study, 30 dipper HT, 31 non-dipper HT patients and 30 healthy control subjects were included. Blood samples were taken for copeptin level determination. All participants underwent detailed cardiovascular and transthoracic echocardiography examinations and measurements of FMD and PWA. Copeptin levels of the non-dipper HT group were significantly higher than the control group and dipper HT groups (P=.001, P=.010, respectively). No significant difference was found between the dipper and non-dipper HT groups regarding FMD and PWA measurements, and both groups significantly differed from the control group. In the whole group evaluation by partial correlation analysis, a significant correlation was found between serum copeptin levels and reflection index (RI) after adjustment for age and body mass index (r=0.24, P=.039). Stepwise linear regression analysis revealed RI as an independent predictor of copeptin (β=0.285, P=.015). The correlation between copeptin levels and RI in HT patients, especially in the non-dipper HT group, suggests that copeptin can be used as a biomarker to indicate endothelial dysfunction in hypertensive patients.

Role of thioredoxin-interacting protein in mediating endothelial dysfunction in hypertension

Hypertension and dyslipidemia frequently coexist, and endothelial dysfunction is associated with the pathophysiology of both atherosclerosis and hypertension. Evidence is convincing for an overlapping role of oxidative stress, renin-angiotensin system activation, and dyslipidemia in the genesis of endothelial dysfunction. Ample experimental and human data suggest that common cellular pathways are involved in the pathogenesis of hypertension, increased vascular resistance, and plaque formation. Multiple interventions such as dietary modification, exercise, antioxidants, and antihypertensive drugs improve endothelial dysfunction in hypertension. Statin drugs are a cornerstone of dyslipidemia therapy. Studies have demonstrated that statins correct endothelial function and vascular stiffening and may be useful in reducing blood pressure to target levels. Statins may be a useful adjunct in the treatment of hypertension in patients with dyslipidemia and possibly those with normal cholesterol levels.

Interference of MDM2 attenuates vascular endothelial dysfunction in hypertension partly through blocking Notch1/NLRP3 inflammasome pathway