Leptin in HIV associated vascular diseases

瘦素在 HIV 相关血管疾病中的作用

• 批准号: 10077588
• 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/10077588
• 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.

项目摘要 联合抗逆转录病毒疗法（cART）在防治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意外地改变了 加速心血管疾病（CVD）的疾病负担，包括动脉粥样硬化， 现在是艾滋病患者死亡的主要原因。引人注目的是，当代cART方案也诱导了 HIV患者的代谢表型从损失（脂肪萎缩）到明显增加， 肥胖症然而，肥胖的增加并没有进一步增加当代HIV患者的CVD风险， 肥胖悖论预防HIV患者CVD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形成的机制，以及 肥胖与HIV-cART相关的血管疾病。在此，我们提供了令人兴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诱导 通过降低血管系统中的瘦素水平和瘦素信号传导来治疗内皮功能障碍。我们发现 氧化剂产生酶Nox 1在血管中的表达，并显示用tempol清除ROS， 或Nox 1的药理学抑制，在我们的HIV和脂肪萎缩的啮齿动物模型中恢复内皮功能。 与此同时，我们报告了在主动脉切片中瘦素信号减少和血管炎症增加， 人类艾滋病患者。值得注意的是，长期瘦素治疗可以显著改善内皮依赖性舒张功能 艾滋病和脂肪萎缩的啮齿动物模型中。此外，瘦素显著降低了Nox 1在大肠杆菌中的表达， 减弱促炎症介质的表达。引人注目的是，内皮细胞中瘦素受体的选择性缺失， 细胞通过Nox 1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剂。我们还报告说， 预防饮食诱导的脂肪组织扩张，而当代cART方案Odefsey显著 在野生型小鼠中增加体重而不诱导内皮功能障碍。这些令人兴奋的 新的发现为这一提议的核心假设提供了信息：艾滋病毒通过破坏动脉粥样硬化， 内皮瘦素信号传导和增加Nox 1表达，这与当代cART相反 保持肥胖和瘦素水平的方案。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 内皮功能改善和血管免疫细胞浸润减少;和（3）HIV和cART 通过TNFα介导的能量消耗控制来调节体重。期望是识别 HIV和cART调节肥胖和动脉粥样硬化形成的分子机制， 预防和治疗与艾滋病毒相关的心血管疾病的途径。