Aortic Stiffness and Hypertension in Obese Mice

肥胖小鼠的主动脉僵硬和高血压

基本信息

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
项目类别：
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

项目摘要

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）：随着年龄或过早的肥胖儿童的增长，动脉僵硬增加了，并且与高血压的发展有关。由于主动脉僵硬将较高的压力传递到周围脉管系统，因此它也可能与高血压的临床并发症有关。我们在正常小鼠中肥胖的初步研究是通过喂养脂肪含量高的饮食（30％）和蔗糖（30％，HFHS），并且是许多美国人所消耗的饮食，并且在10个月后出现了2-4个月的饮食中的主动脉张力和僵硬之间的相关性增加了2-4个月以后，但不存在2个月后。在较早的时间点，HFHS饮食还会损害内皮依赖的松弛，并增加功能上显着的主动脉平滑肌细胞（SMC）蛋白的氧化，包括肌浆网Ca2+ ATPase（SERCA）。当Serca调节SMC对一氧化氮的反应（7NO）时，这表明假设HFHS饮食引起的SMC代谢异常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，这可能与后来的血压发育有关。我们的初步研究还表明，激活主代谢调节剂SIRTUIN-1（SIRT1），放松SMC的多酚以及添加到HFHS饮食中时，可以防止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，氧化剂和刚度受SMC中的SIRT1调节。 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并防止以后的高血压，以及3）使用SMC SIRT1组织特异性缺失的转基因小鼠，测试SMC SIRT1是否是改善主动脉僵硬度和由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

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
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