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; 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）在梳理机会方面取得了非常成功的成功 - 相关疾病并增加预期寿命。但是，购物车意外地改变了 疾病伯恩（Burnen 现在，艾滋病毒患者死亡的主要原因。令人惊讶的是，现代手推车方案也诱发了 HIV患者的代谢表型的急剧转换从损失（脂肪植物）到明显的增益 肥胖。然而，增加的肥胖并不能进一步增加当代艾滋病毒患者的CVD风险，从而产生 肥胖悖论在艾滋病毒中。 HIV患者预防CVD的关键障碍是我们缺乏 理解艾滋病毒和手推车调节肥胖和动脉粥样硬化的机制，以及 HIV-CART相关血管疾病的肥胖。本文中，我们提供令人兴奋的新初步数据 这种HIV病毒感染促进了小鼠的动脉粥样硬化。我们表明病毒感染和脂肪嗜影响 内皮功能障碍通过降低脉管系统中的瘦素水平和瘦素信号传导。我们发现高架 在血管中产生酶Nox1的氧化剂的表达，并表明ROS通过Tempol清除 或NOX1的药理抑制作用，在我们的HIV和脂肪植物啮齿动物模型中恢复内皮功能。 同时，我们报告说，瘦素信号传导降低，主动脉片段中的血管感染增加 人类艾滋病毒患者。值得注意的是，慢性瘦素治疗可鲁棒地改善内皮依赖性松弛 在HIV和脂肪肉芽的啮齿动物模型中。此外，瘦素明显降低了主动脉中的Nox1表达 钝性介导者的表达钝。令人惊讶的是，内皮中瘦素受体的选择性删除 细胞通过NOX1依赖性机制损害内皮功能。最后，我们表明病毒感染 增加TNFα，这是已知的能量消耗的阳性调节剂。我们还报告病毒感染 防止饮食引起的脂肪组织扩张，而现代的手推车方案明显 在野生型小鼠中没有诱发的内皮功能障碍而增加体重。总之，这些令人兴奋的 新发现的结果为这一提议的核心假设提供了信息：HIV通过破坏促进动脉粥样硬化 内皮瘦素信号传导和增强NOX1的表达，这与现代购物车相反 保留肥胖和瘦素水平的方案。我们将在以下特定目的中检验这一假设：（1） 内皮瘦素信号的激活可预防HIV-CART中内皮功能障碍； （2）当代 推车方案通过脂肪 - leptin介导的艾滋病毒小鼠动脉粥样硬化的发展 内皮功能的改善和血管免疫栓塞浸润的减少； （3）艾滋病毒和购物车 通过TNFα介导的能量消耗来调节体重。期望是确定 分子机制，艾滋病毒和手推车调节肥胖和动脉粥样硬化以识别新疗法 与HIV相关的CVD的预防和治疗大道。