Aortic Stiffness and Hypertension in Obese Mice

描述（由申请人提供）：随着年龄的增长或过早肥胖儿童，动脉僵硬度增加，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，因此它也可能与高血压的临床并发症有因果关系。我们在正常小鼠中进行的初步研究通过喂食高脂肪（30%）和蔗糖（30%，HFHS）的饮食而变得肥胖，并且是许多美国人的典型消费，显示主动脉张力增加和僵硬之间的关联在2-4个月的饮食后出现收缩期高血压，在10个月后出现，但在2个月后不存在。在较早的时间点，HFHS饮食还损害内皮依赖性舒张，并增加功能显著的主动脉平滑肌细胞（SMC）蛋白的氧化，包括肌浆网Ca 2 + ATP酶（SERCA）。由于SERCA调节SMC对一氧化氮（7 NO）的反应，这表明HFHS饮食引起的SMC代谢和氧化剂异常可能损害7 NO功能并导致主动脉张力和刚度增加，这可能与高血压的后期发展有因果关系。我们的初步研究还表明，多酚激活主代谢调节因子sirtuin-1（Sirt 1），放松SMC，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HFHS饮食诱导的血管代谢异常、氧化剂和僵硬度受SMC中Sirt 1调节的进一步假设一致。3个目的将1）测试在C57 BL 6小鼠中早期7 NO功能障碍、氧化剂增加和主动脉SMC的僵硬与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的因果关系，2）确定Sirt 1-激活多酚或减少膳食脂肪可以逆转主动脉僵硬的早期代谢介质并预防后期高血压，和3）使用具有SMC Sirt 1的组织特异性缺失的转基因小鼠，测试SMC Sirt 1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。 公共卫生相关性：肥胖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，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。

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.