PREVENTION OF VASCULOPATHY AND NEPHROPATHY IN METABOLIC SYNDROME

预防代谢综合征中的血管病变和肾病

• 批准号: 7341755
• 负责人: MICHAEL S GOLIGORSKY
• 金额: $ 28.76万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341755
• 关键词: 3-nitrotyrosine; Advanced Glycosylation End Products; Aging-Related Process; Animals; Antioxidants; Apoptosis; Apoptotic; Atherosclerosis; Biochemical; CDKN2A gene; Cardiovascular system; Cell Aging; Cell Count; Cell Cycle; Cell Size; Cells; Cessation of life; Collagen; Deceleration; Development; Diabetes Mellitus; Disruption; Endothelial Cells; Enrollment; Epidemic; Event; Extracellular Matrix Proteins; Extravasation; Fatty acid glycerol esters; Fructose; Functional disorder; Galactosidase; Gangliosides; General Population; Human; Image Analysis; In Vitro; Incidence; Insulin Resistance; Investigation; Kidney; Kidney Diseases; Lead; Life; Light; Mediating; Metabolic; Metabolic syndrome; Microcirculation; Mitochondria; Modeling; Molecular; Molecular Target; Morphology; Mus; North America; Obesity; Oxidative Stress; Oxygen Consumption; Pathway interactions; Patients; Permeability; Peroxonitrite; Personal Satisfaction; Phase II Clinical Trials; Phenotype; Population; Premature aging syndrome; Prevention; Production; Protein Kinase C; Proteins; Rattus; Role; Superoxides; Syndrome; TP53 gene; Techniques; Treatment Efficacy; Tumor Necrosis Factor-alpha; Umbilical vein; Video Microscopy; activation product; antioxidant therapy; base; concept; day; design; diabetic; diabetic rat; ebselen; feeding; human TNF protein; in vivo; intravital fluorescence microscopy; mitochondrial dysfunction; non-diabetic; oxidized low density lipoprotein; prevent; receptor for advanced glycation endproducts; research study; senescence

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.

糖尿病患者心血管系统的加速动脉粥样硬化和过早老化 糖尿病和代谢综合征已成为流行病。我们以前对内皮细胞的研究 在模拟糖尿病微环境的微环境中，细胞显示了 细胞衰老基于硝基酪氨酸修饰的蛋白质的表达被抑制的观察， 增强在过早衰老的细胞和过氧亚硝酸盐处理的完整细胞导致过早 衰老时，我们用真正的过氧亚硝酸盐清除剂/抗氧化剂依布硒啉处理内皮细胞。 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细胞过早衰老的分子机制， 依布硒啉对代谢综合征- Zucker糖尿病模型中内皮细胞过早衰老的影响 大鼠，并检查这些动物中血管病变的发展。我们假设氧化 应激/过氧亚硝酸盐诱导溶酶体功能障碍引发内皮细胞衰老和积累 神经节苷脂，从衰老到凋亡的分子开关-事件支持的进展， 血管病变采用图像分析和荧光活体显微镜的体外和体内研究， 生化技术检测溶酶体和线粒体的泄漏！蛋白质以及积累 并对细胞周期标志物进行定量分析， 以及早衰和凋亡的细胞机制。Zucker糖尿病脂肪的体内研究 用依布硒啉治疗大鼠，以检查预防和逆转宏观和 微血管病变（肾病）。这些研究可能有助于阐明 内皮细胞的过早衰老，过氧亚硝酸盐在启动它中的作用，以及潜在的治疗 过氧亚硝基阴离子清除在改善血管病变中的功效。