Aortic Stiffness and Hypertension in Obese Mice

肥胖小鼠的主动脉僵硬和高血压

• 批准号: 8149954
• 负责人: RICHARD A COHEN
• 金额: $ 40.88万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149954
• 关键词: Address; Age; American; Atherosclerosis; Blood Pressure; Blood Vessels; Boston; Ca(2+)-Transporting ATPase; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Child; Clinical; Development; Diet; Dietary Fats; Elderly; Endothelial Cells; Endothelium; Environment; Fatty acid glycerol esters; Functional disorder; Funding; Hindlimb; Hypertension; In Vitro; Institutes; Lead; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Mus; Nitric Oxide; Obese Mice; Obesity; Oxidants; Peripheral; Physiologic pulse; Proteins; Relaxation; Research; Research Personnel; Role; Sarcoplasmic Reticulum; Smooth Muscle; Smooth Muscle Myocytes; Sucrose; Testing; Time; Tissues; Transgenic Mice; Ultrasonography; United States National Institutes of Health; Universities; angiogenesis; arterial stiffness; experience; feeding; improved; in vivo; oxidation; polyphenol; premature; pressure; prevent; programs; public health relevance; response; systolic hypertension; therapeutic target

DESCRIPTION (provided by applicant): With advancing age or prematurely in obese children, arterial stiffness increases and has been implicated in the development of hypertension. Because the aortic stiffness transmits higher pressure to the peripheral vasculature, it may also be causally related to the clinical complications of hypertension. Our preliminary studies in normal mice made obese by feeding a diet which is high in fat (30%) and sucrose (30%, HFHS), and is typical of that consumed by many Americans, show an association between increased aortic tone and stiffness present after 2-4 months of diet with systolic hypertension that is present after 10 months, but not after 2 months. At the earlier time point HFHS diet also impairs endothelium-dependent relaxation and increases oxidation of functionally significant aortic smooth muscle cell (SMC) proteins, including the sarcoplasmic reticulum Ca2+ ATPase (SERCA). As SERCA regulates the SMC response to nitric oxide (7NO), this suggests the hypothesis that abnormalities in SMC metabolism and oxidants caused by HFHS diet may impair 7NO function and lead to increased aortic tone and stiffness that may be causally related to the later development of hypertension. Our preliminary studies also show that polyphenols which activate the master metabolic regulator, sirtuin-1 (Sirt1), relax SMC and when added to HFHS diet, prevent both the early abnormalities in aortic tone and oxidants, as well as the late hypertension. This is consistent with the further hypothesis that HFHS diet-induced vascular metabolic abnormalities, oxidants, and stiffness are regulated by Sirt1 in SMC. The 3 aims will 1) test if there is a temporal and potentially causal relationship between the early 7NO dysfunction, increased oxidants, and stiffness of aortic SMC with the later development of systolic hypertension associated with obesity induced by HFHS diet in C57BL6 mice, 2) determine if a Sirt1-activating polyphenol or dietary fat reduction can reverse early metabolic mediators of aortic stiffness and prevent later hypertension, and 3) using transgenic mice with tissue-specific deletion of SMC Sirt1, test if SMC Sirt1 is a potential therapeutic target for improving aortic stiffness and hypertension caused by obesity. PUBLIC HEALTH RELEVANCE: Obesity increases the complications of cardiovascular disease, including aortic stiffness and hypertension. Our studies will determine how oxidants arising from tissue metabolism in obese mice increase aortic stiffness and cause hypertension. As aortic stiffness precedes hypertension, we will test if ameliorating aortic oxidants and stiffness at a younger age can prevent the later development of hypertension.

描述（由申请人提供）：随着年龄的增长或肥胖儿童的早产，动脉僵硬度会增加，并与高血压的发展有关。由于主动脉僵硬将较高的压力传递至周围脉管系统，因此它也可能与高血压的临床并发症有因果关系。我们对正常小鼠的初步研究表明，通过喂食高脂肪（30%）和高蔗糖（30%，HFHS）的饮食而导致肥胖，这是许多美国人食用的典型饮食，结果显示，主动脉张力增加和饮食 2-4 个月后出现的僵硬与收缩性高血压之间存在关联，收缩性高血压在 10 个月后出现，但在 2 个月后则不再出现。在较早的时间点，HFHS 饮食还会损害内皮依赖性舒张，并增加功能重要的主动脉平滑肌细胞 (SMC) 蛋白的氧化，包括肌浆网 Ca2+ ATP 酶 (SERCA)。由于 SERCA 调节 SMC 对一氧化氮 (7NO) 的反应，这表明 HFHS 饮食引起的 SMC 代谢和氧化剂异常可能会损害 7NO 功能并导致主动脉张力和僵硬度增加，这可能与后来发生高血压有因果关系。我们的初步研究还表明，多酚可以激活主要代谢调节剂 Sirtuin-1 (Sirt1)，放松 SMC，并且当添加到 HFHS 饮食中时，可以预防主动脉张力和氧化剂的早期异常以及晚期高血压。这与进一步的假设是一致的，即 HFHS 饮食诱导的血管代谢异常、氧化剂和僵硬度是由 SMC 中的 Sirt1 调节的。这 3 个目标将 1) 测试早期 7NO 功能障碍、氧化剂增加和主动脉 SMC 僵硬与 C57BL6 小鼠中 HFHS 饮食诱导的肥胖相关的收缩期高血压的后期发展之间是否存在时间和潜在因果关系，2) 确定 Sirt1 激活多酚或膳食脂肪减少是否可以逆转主动脉僵硬的早期代谢介质 并预防以后的高血压，3）使用组织特异性删除 SMC Sirt1 的转基因小鼠，测试 SMC Sirt1 是否是改善主动脉僵硬和肥胖引起的高血压的潜在治疗靶点。 公共卫生相关性：肥胖会增加心血管疾病的并发症，包括主动脉僵硬和高血压。我们的研究将确定肥胖小鼠组织代谢产生的氧化剂如何增加主动脉僵硬度并导致高血压。由于主动脉僵硬先于高血压发生，我们将测试在年轻时改善主动脉氧化剂和僵硬是否可以预防高血压的后期发展。