Leptin in HIV associated vascular diseases

瘦素在 HIV 相关血管疾病中的作用

• 批准号: 10321549
• 负责人: Eric J Belin de Chantemele
• 金额: $ 49.84万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321549
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Adipose tissue; Affect; Animal Model; Animals; Antioxidants; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Body Weight; CCR5 gene; Cardiovascular Diseases; Cause of Death; Cells; Chronic; Data; Development; Diet; Disease; Endothelial Cells; Endothelium; Energy Metabolism; Enzymes; Etanercept; Exhibits; Genetic Engineering; HIV; HIV tat Protein; Hormones; Human; Immune; Impairment; Infection prevention; Infiltration; Inflammation Mediators; Infusion procedures; Interleukin-1 beta; Leptin; Life Expectancy; Lipoatrophy; Mediating; Molecular; Mus; Obesity; Outcome; Oxidants; Patients; Pharmacology; Prevention; Public Health; Regimen; Relaxation; Reporting; Rodent Model; Role; Sampling; Signal Transduction; TNF gene; Testing; Tissue Expansion; Vascular Diseases; Virus Diseases; Weight Gain; Wild Type Mouse; antiretroviral therapy; atherogenesis; burden of illness; cardiovascular disorder prevention; cardiovascular disorder risk; endothelial dysfunction; expectation; improved; leptin receptor; metabolic phenotype; mortality; mouse model; novel; novel therapeutics; preservation; prevent; tat Protein; tempol; vascular inflammation

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.

项目概要 联合抗逆转录病毒疗法 (cART) 在对抗机会性艾滋病方面取得了巨大成功 然而，cART 却出人意料地改变了治疗范围。 疾病负担加速心血管疾病（CVD），包括动脉粥样硬化，这是 引人注目的是，当代的 cART 治疗方案也导致了 HIV 患者死亡。 HIV 患者的代谢表型发生了巨大转变，从脂肪减少（脂肪萎缩）到明显增加 然而，肥胖的增加并不会进一步增加当代 HIV 患者的 CVD 风险，从而导致 HIV-cART 中的肥胖悖论是预防 HIV 患者 CVD 的一个关键障碍。 了解 HIV 和 cART 调节肥胖和动脉粥样硬化形成的机制，以及 在此，我们提供了令人兴奋的新初步数据表明肥胖与 HIV-cART 相关的血管疾病。 HIV病毒感染会促进小鼠动脉粥样硬化 我们发现病毒感染和脂肪萎缩会导致小鼠动脉粥样硬化。 我们发现血管系统中的瘦素水平和瘦素信号传导升高，从而导致内皮功能障碍。 血管中氧化剂生成酶 Nox1 的表达，并表明 tempol 可以清除 ROS， 或 Nox1 的药理学抑制，可恢复我们的 HIV 和脂肪萎缩啮齿动物模型中的内皮功能。 与此同时，我们报告了主动脉切片中瘦素信号减少和血管炎症增加 值得注意的是，长期瘦素治疗可显着改善内皮依赖性松弛。 此外，在 HIV 和脂肪萎缩的啮齿动物模型中，瘦素显着降低了主动脉和脂肪组织中 Nox1 的表达。 显着地抑制内皮细胞中瘦素受体的表达。 细胞通过 Nox1 依赖性机制损害内皮功能 最后，我们证明了病毒感染。 增加 TNFα，这是一种已知的能量消耗正调节因子。我们还报告了病毒感染。 防止饮食引起的脂肪组织扩张，而当代 cART 方案 Odefsey 显着 总的来说，这些令人兴奋的结果是在野生型小鼠中增加体重而不引起内皮功能障碍。 新颖的发现为该提案的核心假设提供了依据：艾滋病毒通过扰乱促进动脉粥样硬化 内皮瘦素信号传导和增强 Nox1 表达，这是当代 cART 所反对的 我们将在以下具体目标中检验这一假设：（1） 内皮瘦素信号传导的激活可防止 HIV-cART 中的内皮功能障碍 (2) 现代； 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 改善内皮功能并减少血管免疫细胞浸润；(3) HIV 和 cART 通过 TNFα 介导的能量消耗控制来调节体重。 HIV 和 cART 调节肥胖和动脉粥样硬化形成的分子机制，以确定新的治疗方法 预防和治疗与 HIV 相关的 CVD 的途径。