Apoptosis and vascular remodeling

Cell death by apoptosis plays a major role in the homeostasis of the vascular system. Apoptosis of vascular cells, and of endothelial and smooth muscle cells, can be triggered by intrinsic signals related to the cell differentiation phenotype, or by extrinsic signals, including free radicals, inflammatory cytokines or oxidized LDL. Apoptosis contributes to normal physiological modelling of arteries after birth as well as to capillary rarefaction occurring during ontogenic development. Apoptotic processes have been found in several pathological conditions, including atherosclerosis, hypertension or restenosis following percutaneous transluminal angioplasty. However, a direct causal relationship between apoptosis and occurrence of these afflictions remains to be established.     

骨桥蛋白与血管重塑

背景:骨桥蛋白是细胞外基质中的磷酸化糖蛋白,在骨形成及重建过程中起重要作用,近年来骨桥蛋白在抗炎和损伤修复、血管重塑过程中的作用逐渐引起人们的重视.目的:综合分析骨桥蛋白在血管重塑中的作用.方法:计算机检索外文期刊整合服务系统和中国期刊全文数据库中有关骨桥蛋白对血管增殖性疾病影响的文献,并分析其对血管重塑过程的研究进展.结果与结论:骨桥蛋白通过其黏附基序与整合素相互作用,调节细胞黏附、迁移、增殖等多种生物学行为,可通过调节血管平滑肌细胞的增殖、分化、黏附、迁移和营养不良性钙化等不同途径调节血管重塑.适度有效地抑制骨桥蛋白的激活将有望成为防治血管增殖性疾病的策略之一.     

The cardioprotective effects of mineralocorticoid receptor antagonists

Despite state-of-the-art reperfusion therapy, morbidity and mortality remain significant in patients with an acute myocardial infarction. Therefore, novel strategies to limit myocardial ischemia–reperfusion injury are urgently needed. Mineralocorticoid receptor (MR) antagonists are attractive candidates for this purpose, since several clinical trials in patients with heart failure have reported a survival benefit with MR antagonist treatment. MRs are expressed by several cells of the cardiovascular system, including cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, and endothelial cells. Experiments in animal models of myocardial infarction have demonstrated that acute administration of MR antagonists, either before ischemia or immediately at the moment of coronary reperfusion, limits infarct size. This action appears to be independent of the presence of aldosterone and cortisol, which are the endogenous ligands for the MR. The cardioprotective effect is mediated by a nongenomic intracellular signaling pathway, including adenosine receptor stimulation, and activation of several components of the Reperfusion Injury Salvage Kinase (RISK) pathway. In addition to limiting infarct size, MR antagonists can improve scar healing when administered shortly after reperfusion and can reduce cardiac remodeling post myocardial infarction. Clinical trials are currently being performed studying whether early administration of MR antagonists can indeed improve prognosis in patients with an acute myocardial infarction, independent of the presence of heart failure.     

Immunohistochemical localization of mineralocorticoid receptor in human gut.

Immunohistochemical localization of mineralocorticoid receptor in the human adult gut was examined by using a polyclonal antibody raised against a mineralocorticoid receptor fusion protein. Immunoreactive staining was observed in columnar cells in the middle of the intestinal glands of the proximal colon, but not in goblet cells. Western blot analysis also revealed the presence of an approximately 100 kDa immunoreactive species consistent with the mineralocorticoid receptor protein in the ascending colon as well as the kidney. These results suggest that aldosterone-sensitive sodium transport and water absorption may be mainly carried out in the proximal colon in human adult gut at non-pathological state.     

The effects of caffeic acid phenethyl ester and melatonin on age-related vascular remodeling and cardiac damage

Oxidative stress has been implicated with cardiovascular aging. Most antioxidant intervention studies have involved long-term treatments as a potential means to eliminate age-related oxidative damage in many systems. In the present study, not only light and electron microscopic pictures of the heart and thoracic aorta of young and aged and, caffeic acid phenethyl ester (CAPE) and melatonin and administered aged Sprague Dawley rats, but also antioxidant system status was evaluated. Significantly elevated levels of malondialdehyde (MDA) were observed in the heart and thoracic aorta of aged rats (P<0.05 and P<0.001, respectively). Chronic melatonin and CAPE administration significantly reduced the levels of MDA in the heart (P=0.005 and P=0.05, respectively) and thoracic aorta (P<0.001 and P<0.05, respectively) of aged animals. Additionally, melatonin and CAPE were efficient in stimulating the activities and increasing the levels of the antioxidant enzymes in the heart and aorta. Prominent electron microscopic alterations in cardiac myocytes such as nuclear irregularity, mitochondrial degeneration, myofilament disorganization and disruption, and lipofuscin accumulation were observed in aged rats. The main age-related histologic modifications observed in aorta were irregularity in endothelial cells and their nuclei, divergence of endothelial cells from basement membrane and neighboring cells, and elastic fibril fragmentation and reduction. Melatonin and CAPE obviously reduced these alterations in both heart and aorta of aged rats. Taking the results together, we suggest that supplemental administration of CAPE and melatonin is beneficial in delaying age-related cellular damage in cardiovascular system.     

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.     

Vasoactive substance and vascular remodeling]

Vascular remodeling is characterized by the dysfunction of endothelial cells, vascular smooth muscle cell (SMC) proliferation and migration, and the increased accumulation of extracellular matrix. Angiotensin II causes SMC growth and migration, and stimulates the expression of vascular remodeling-related genes. Angiotensin II activates a diversity of intracellular signal transduction cascades, and transactivation of epidermal growth factor and platelet-derived growth factor receptors via AT1 receptor seems to be responsible for the development of vascular remodeling. Not only angiotensin II but also endothelin-1, nitric oxide, c-type natriuretic peptide and adrenomedullin play an important role in the development of vascular remodeling.     

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*

OBJECTIVE:: This study tested the hypothesis that interruption of the renin-angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the prevalence of atrial fibrillation after cardiac surgery. DESIGN:: Randomized double-blind placebo-controlled study. SETTING:: University-affiliated hospitals. PATIENTS:: Four hundred forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. INTERVENTIONS:: One week to 4 days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5mg the first 3 days followed by 5mg/day, with the dose reduced to 2.5mg/day on the first postoperative day only), or spironolactone (25mg/day). MEASUREMENTS:: The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the prevalence of hypotension, length of hospital stay, stroke, and death. MAIN RESULTS:: The prevalence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (p = .95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, p = .006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days vs. 5.7±3.2 days and 5.8±3.4 days, respectively, p = .08 for the comparison of placebo vs. the active treatment groups using log-rank test). Compared with patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 mins vs. 1091.3±3067.3 mins, p = .04). CONCLUSIONS:: Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.