MOLECULAR MECHANISM OF ADIPONECTIN-DEFICIENCY ON HYPERTENSION AND CARDIVASCULAR REMODELING

脂联素缺乏对高血压和心血管重塑的分子机制

基本信息

批准号：
17590960
负责人：
KIHARA Shinji
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590960/
关键词：
GENE INTERNAL MEDICINE CARDIOVASCULAR HYPERTENSION DIABETES MELLITUS PROTEOME

项目摘要

This study was designed to elucidate the molecular mechanism of hypoadiponectinemia on the development of hypertension and cardiovascular remodeling with adiponectin deficient mice. Adiponectin deficient mice developed hypertension when maintained on a high-salt diet without insulin resistance. The hypertension of salt-fed adiponectin deficient mice was associated with the impaired induction of endothelial NO synthase mRNA level in the systemic vasculature. Adiponectin therapy lowered the elevated blood pressure and increased endothelial NO synthase. Ischemia-reperfusion in adiponectin deficient mice resulted in increased myocardial infarct size. Administration of adiponectin diminished infarct size. Adiponectin suppressed myocardial apoptosis and tumor necrosis factor-alpha expression through AMP-activated protein kinase and cyclooxygenase pathways, respectively. In human aortic endothelial cells, adiponectin suppressed inflammatory cytokine IL-8 production, which may mediate adiponectin inhibition of atherosclerosis. In addition, as clinical significance of adiponectin, we found that 1) Angiotensin II type-1 receptor blocker increased plasma adiponectin level by targeting oxidative stress in adipose tissue, 2) Smoking habit was associated decreased adiponectin level, and oxidative stress and nicotine reduced adiponectin mRNA in adipocytes, 3) Thiazolidinedione treatment improved left ventricular diastolic function without left ventricular mass regression in hypertensive patients in proportion to the amelioration of insulin resistance, 4) Adiponectin was decreased in patients with peripheral arterial occlusive disease in proportion to the severity of the disease, 5) Renal function was a significant regulator of adiponectin when categorized by chronic kidney disease stages, whereas hypoadiponectinemia was a predictor of cardiovascular disease. These results provide an adiponectin mediated novel molecular basis of hypertension and cardiovascular remodeling.

本研究旨在阐明低脂联素血症对脂联素缺陷小鼠发生高血压和心血管重塑的分子机制。脂联素缺乏的小鼠在维持高盐饮食且没有胰岛素抵抗的情况下会出现高血压。盐饲脂联素缺乏小鼠的高血压与全身脉管系统中内皮NO合酶mRNA水平的诱导受损有关。脂联素治疗可降低升高的血压并增加内皮一氧化氮合酶。脂联素缺陷小鼠的缺血再灌注导致心肌梗塞面积增加。施用脂联素可缩小梗塞面积。脂联素分别通过 AMP 激活的蛋白激酶和环氧合酶途径抑制心肌细胞凋亡和肿瘤坏死因子-α 表达。在人主动脉内皮细胞中，脂联素抑制炎症细胞因子IL-8的产生，这可能介导脂联素抑制动脉粥样硬化。此外，作为脂联素的临床意义，我们发现：1) 血管紧张素 II 1 型受体阻滞剂通过靶向脂肪组织中的氧化应激来增加血浆脂联素水平，2) 吸烟习惯与脂联素水平降低相关，氧化应激和尼古丁降低脂联素水平脂肪细胞中的 mRNA，3) 噻唑烷二酮治疗可改善高血压患者的左心室舒张功能，且左心室质量不会消退与胰岛素抵抗的改善成正比，4) 外周动脉闭塞性疾病患者的脂联素下降与疾病的严重程度成正比，5) 按慢性肾脏病阶段分类时，肾功能是脂联素的重要调节因子，而低脂联素血症则与心血管疾病的预测因子。这些结果提供了脂联素介导的高血压和心血管重塑的新分子基础。