Aortic Stiffness and Hypertension in Obese Mice

肥胖小鼠的主动脉僵硬和高血压

• 批准号: 8484428
• 负责人: RICHARD A COHEN
• 金额: $ 38.57万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484428
• 关键词: Address; Age; American; Atherosclerosis; Blood Pressure; Blood Vessels; Boston; Ca(2+)-Transporting ATPase; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; 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; obesity in children; 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.

描述(由申请人提供)：随着肥胖儿童年龄的增加或过早，动脉僵硬增加，并与高血压的发展有关。由于主动脉僵硬将更高的压力传递到外周血管系统，它也可能与高血压的临床并发症有关。我们对正常小鼠的初步研究表明，在饮食中摄入高脂肪(30%)和高蔗糖(30%，HFHS)的食物造成肥胖，这是许多美国人典型的饮食，表明饮食2-4个月后主动脉张力增加和僵硬之间存在关联，10个月后出现收缩压升高，但2个月后不存在。在早期时间点，HFHS饮食还损害内皮依赖的松弛，并增加具有重要功能的主动脉平滑肌细胞(SMC)蛋白的氧化，包括肌浆网钙ATPase(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代谢和氧化剂的异常可能损害了7NO的功能，导致主动脉张力和僵硬增加，这可能与高血压的后期发展有关。我们的初步研究还表明，激活主要代谢调节因子sirtuin-1(Sirt1)的多酚可以松弛SMC，当添加到HFHS饮食中时，可以预防早期主动脉张力和氧化剂的异常，以及晚期高血压。这与进一步的假设一致，即HFHS饮食诱导的血管代谢异常、氧化剂和僵硬是由Sirt1在SMC中调节的。这3个目标将1)测试早期的7NO功能障碍、氧化剂增加和主动脉SMC僵硬与HFHS饮食诱导的C57BL6小鼠肥胖相关的晚期收缩高血压之间是否存在时间和潜在的因果关系；2)确定Sirt1激活的多酚或饮食降脂是否可以逆转主动脉僵硬的早期代谢介质，防止后期高血压；以及3)使用组织特异性SMC Sirt1缺失的转基因小鼠，测试SMC Sirt1是否是改善肥胖引起的主动脉僵硬和高血压的潜在治疗靶点。

项目成果

Vascular Smooth Muscle Sirtuin-1 Protects Against Diet-Induced Aortic Stiffness.

• DOI: 10.1161/hypertensionaha.116.07622
• 发表时间: 2016-09
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Fry JL;Al Sayah L;Weisbrod RM;Van Roy I;Weng X;Cohen RA;Bachschmid MM;Seta F
• 通讯作者: Seta F