PREVENTION OF VASCULOPATHY AND NEPHROPATHY IN METABOLIC SYNDROME

糖尿病患者动脉粥样硬化加速和心血管系统早衰 糖尿病和代谢综合征已经达到流行的程度。我们之前对内皮细胞的研究 在模拟糖尿病环境的微环境中，细胞显示出加速的发展 细胞衰老。基于观察到的硝基酪氨酸修饰蛋白的表达 增强了早衰细胞和过氧亚硝酸盐处理的完整细胞导致早产 在衰老过程中，我们用真正的过氧亚硝酸盐清除剂/抗氧化剂ebselen处理内皮细胞。 这种治疗与预防和逆转早衰有关。这些 这些发现促使我们研究了细胞过早衰老的分子机制(S)， 依贝塞林对代谢综合征-Zucker糖尿病模型血管内皮细胞早衰的影响 并检查这些动物血管病变的发展情况。我们假设氧化剂 应激/过氧亚硝酸盐诱导的溶酶体功能障碍启动内皮细胞衰老和积聚 神经节苷脂，一种从衰老到细胞凋亡的分子开关-支持血管内皮细胞瘤进展的事件 血管病变。利用图像分析和荧光活体显微镜进行的体外和体内研究， 检测溶酶体和线粒体渗漏的生化技术！蛋白质和积累 神经节苷脂和细胞周期标志物的定量分析用于研究分子 以及过早衰老和细胞凋亡的细胞机制。Zucker糖尿病脂肪的体内研究 Ebselen处理的大鼠将被用来研究预防和逆转宏观和微观结构的可能性。 此综合征中的微血管病变(肾病)。这些调查可能会揭示出 内皮细胞早衰、过氧亚硝酸盐在其启动中的作用及潜在的治疗方法 过氧亚硝酸盐清除对血管病变的改善作用。

Accelerated atherosclerosis and premature aging of the cardiovascular system in patients with diabetes mellitus and metabolic syndrome have acquired epidemic proportions. Our previous studies of endothelial cells subjected to a microenvironment emulating the diabetic milieu revealed accelerated development of cell senescence. Based on the observations that the expression of nitrotyrosine-modified proteins was enhanced in the prematurely senescent cells and peroxynitrite treatment of intact cells led to premature senescence, we treated endothelial cells with a bona fide peroxynitrite scavenger/antioxidant ebselen. Such a treatment was associated with the prevention and reversal of premature senescence. These findings prompted us to investigate the molecular mechanism(s) of premature cell senescence, effects of ebselen on premature endothelial cell senescence in a model of metabolic syndrome - Zucker diabetic rats, and examine the development of vasculopathy in these animals. We hypothesize that oxidative stress/peroxynitrite-induced lysosomal dysfunction initiates endothelial cell senescence and accumulation of gangliosides, a molecular switch from senescence to apoptosis- events underpinning the progression of vasculopathy. In vitro and in vivo studies employing image analysis and fluorescence intravital microscopy, biochemical techniques to detect leakage of lysosomal and mitochondria! proteins as well as accumulation of gangliosides, and quntitative analysis of the markers of cell cycle are designed to investigate molecular and cellular mechanisms of premature senescence and apoptosis. In vivo studies of the Zucker diabetic fat rat treated with ebselen will be conducted to examine the possibility of preventing and reversing macro- and micro-vasculopathy (nephropathy) in this syndrome. The investigations may shed light on mechanisms of premature senescence of endothelial cells, role of peroxynitrite in initiating it, and potential therapeutic efficacy of peroxynitrite scavenging in amelioration of vasculopathy.