Leptin in HIV associated vascular diseases

项目总结 联合抗逆转录病毒疗法(CART)在抗击机会性艾滋病方面取得了显著成功。 相关疾病和预期寿命的增加。然而，Cart出人意料地改变了 疾病负担加速心血管疾病(CVD)，包括动脉粥样硬化，这是 现在是艾滋病毒患者死亡的主要原因。引人注目的是，当代的CART养生法也导致了 HIV患者代谢表型从丢失(脂肪萎缩)到显著增加 肥胖症。然而，肥胖增加并不会进一步增加当代艾滋病毒患者患心血管疾病的风险，从而造成 艾滋病购物车中的肥胖悖论。预防艾滋病毒患者心血管疾病的一个关键障碍是我们缺乏 了解HIV和CART调节肥胖和动脉粥样硬化的机制，以及 HIV-CART相关血管疾病中的肥胖症。在此，我们提供了令人振奋的新的初步数据，表明 HIV病毒感染会促进小鼠的动脉粥样硬化。我们发现病毒感染和脂肪萎缩会导致 通过减少血管中瘦素水平和瘦素信号而导致的内皮功能障碍。我们发现被提升了 氧化产生酶Nox1在血管中的表达，并表明Temol清除ROS， 或药物抑制NOX1，恢复我们的艾滋病毒和脂肪萎缩啮齿动物模型的内皮功能。 同时，我们报告了瘦素信号的减少和血管炎症的增加。 人类艾滋病患者。值得注意的是，慢性瘦素治疗有力地改善了内皮依赖的松弛 在HIV和脂肪萎缩的啮齿动物模型中。此外，瘦素显著降低了主动脉中Nox1的表达，并 钝化促炎介质的表达。值得注意的是，内皮细胞中瘦素受体的选择性缺失 细胞通过依赖Nox1的机制损害内皮功能。最后，我们证明了病毒感染 增加肿瘤坏死因子α，这是一种已知的能量消耗的积极调节因素。我们还报告说，病毒感染 防止饮食诱导的脂肪组织扩张，而当代CART方案奥德西显著 在不引起野生型小鼠内皮功能障碍的情况下增加体重。总而言之，这些令人兴奋的 新的发现为这一提议的核心假设提供了依据：艾滋病毒通过破坏 内皮瘦素信号和增强Nox1的表达，这是当代CART反对的 保持肥胖和瘦素水平的养生法。我们将在以下具体目标上检验这一假设：(1) 激活内皮瘦素信号保护HIV-CART中的内皮功能障碍；(2)当代 CART方案通过脂肪-瘦素介导预防HIV小鼠动脉粥样硬化的发展 血管内皮功能的改善和血管免疫细胞浸润的减少；以及(3)HIV和CART 通过肿瘤坏死因子α介导的能量消耗控制来调节体重。我们的期望是确定 HIV和CART调节肥胖和动脉粥样硬化的分子机制以寻找新的治疗方法 预防和治疗与艾滋病毒相关的心血管疾病的大道。

PROJECT SUMMARY Combination antiretroviral therapy (cART) has been remarkably successful in combating opportunistic AIDS- related diseases and increasing life expectancy. However, cART has unexpectedly shifted the spectrum of disease burden towards an acceleration of cardiovascular diseases (CVD), including atherosclerosis, which is now the leading cause of mortality in HIV patients. Strikingly, contemporary cART regimens have also induced a drastic switch in the metabolic phenotype of HIV patients from a loss (lipoatrophy) to a pronounced gain in adiposity. Yet, increased adiposity does not further augment CVD risk in contemporary HIV patients, creating an obesity paradox in HIV-cART. A critical barrier to the prevention of CVD in HIV patients is our lack of understanding of the mechanisms whereby HIV and cART regulate adiposity and atherogenesis, and the role of adiposity in HIV-cART-associated vascular diseases. Herein, we provide exciting new preliminary data indicating that HIV viral infection promotes atherosclerosis in mice. We show that viral infection and lipoatrophy induce endothelial dysfunction by reducing leptin levels and leptin signaling in the vasculature. We find elevated expression of the oxidant generating enzyme Nox1 in blood vessels and show that ROS scavenging with tempol, or pharmacological inhibition of Nox1, restores endothelial function in our rodent models of HIV and lipoatrophy. In parallel, we report decreased leptin signaling and increased vascular inflammation in aortic sections from human HIV patients. Remarkably, chronic leptin treatment robustly improves endothelium-dependent relaxation in rodent models of HIV and lipoatrophy. Moreover, leptin markedly reduces Nox1 expression in aortae and blunts expression of pro-inflammation mediators. Strikingly, selective deletion of the leptin receptor in endothelial cells impairs endothelial function via a Nox1-dependent mechanism. Lastly, we show that viral infection increases TNFα which is a known positive regulator of energy expenditure. We also report that viral infection prevents diet-induced adipose tissue expansion, while the contemporary cART regimen Odefsey markedly increases body weight without inducing endothelial dysfunction in wild-type mice. Taken together, these exciting and novel findings inform the core hypothesis of this proposal: HIV promotes atherosclerosis by disrupting endothelial leptin signaling and augmenting Nox1 expression, which is opposed by contemporary cART regimens that preserve adiposity and leptin levels. We will test this hypothesis in the following specific aims: (1) Activation of endothelial leptin signaling protects against endothelial dysfunction in HIV-cART; (2) Contemporary cART regimens prevent the development of atherosclerosis in HIV mice via adipose-leptin mediated improvement in endothelial function and reduction in vascular immune cell infiltration; and (3) HIV and cART regulate body weight via TNFα-mediated control of energy expenditure. The expectation is to identify the molecular mechanisms whereby HIV and cART regulate adiposity and atherogenesis to identify new therapeutic avenue for the prevention and treatment of CVD- associated with HIV.