Diastolic dysfunction in HIV infection

HIV感染者的舒张功能障碍

• 批准号: 10250637
• 负责人: KESHORE R BIDASEE
• 金额: $ 58.64万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250637
• 关键词: Adhesions; Animal Model; Anti-Retroviral Agents; Area; Attenuated; Autopsy; Biological Markers; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Culture Techniques; Cells; Chemicals; Clinical; Coronary; DNA; Data; Dependovirus; Development; Disease; Down-Regulation; Dyspnea; Echocardiography; Endothelin-1; Engineering; Enzymes; Extravasation; Fibrosis; Functional disorder; Glycolysis; HIV; HIV Infections; HIV-1; Heart; Heart Diseases; Heart failure; Homeostasis; Hospitalization; Human; Immune system; Impairment; Incidence; Infection; Inflammasome; Inflammation; Inflammatory; Intervention; Ischemia; Kinetics; Laboratories; Lactoylglutathione Lyase; Link; Lung; Modeling; Molecular; Mus; Muscle Cells; Myocardial dysfunction; Myocarditis; NF-kappa B; National NeuroAids Tissue Consortium; Outcome; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Physiologic pulse; Plasma; Proteins; Protocols documentation; Pyruvaldehyde; Relaxation; Research; Secondary to; Study models; Therapeutic; Time; Tissues; Transcription Factor AP-1; Up-Regulation; Ventricular; Viremia; adduct; base; clinically relevant; cytotoxic; early onset; heart function; humanized mouse; in vivo; middle age; mouse model; novel; overexpression; prevent; promoter; reconstitution; sudden cardiac death; tissue/cell culture

Abstract: More than 25% of middle-aged people living with HIV-1 infection (PLWH) have early onset myocardial diseases including diastolic dysfunction (DD), harbingers for symptomatic heart failure, dyspnea, pulmonary abnormalities, frequent hospitalizations, and sudden cardiac death.8-16 To date, the molecular causes for the myocardial dysfunction in PLWH remain poorly understood. This paucity of information and a lack of treatment options have prompted the OAR to list “Strategies to Prevent and Treat HIV-Associated Heart Diseases” as areas of high priority for HIV research. We hypothesize that “early onset myocardial dysfunction in PLWH is arising from accumulation of cytotoxic glycolysis metabolite, methylglyoxal (MG) as a result of persistent cardiac inflammation.” This hypothesis is based on several lines of new evidence recently obtained in our laboratories. First, HIV-1 infected humanized NOD/Scid-IL2Rg-/-(NSG) mice reconstituted with human immune system (Hu-NSG) develop a progressive cardiomyopathy akin to that seen in patients. Second, cART lowers plasma HIV-1 viremia but does not lower cardiac inflammation indicated by upregulation of the inflammation-biomarker, vascular adhesion protein-1 (VAP-1). Third, the cytotoxic glycolysis by-product MG, accumulated in hearts of HIV-1 infected Hu-NSG mice with/without cART due to inflammation-induced downregulation of MG-degrading enzyme glyoxalase-1 (Glo1). Elevated MG form MG-H1 adduct on proteins. Fourth, increased VAP-1 and MG-H1, and reduced Glo1 were found in autopsied ventricular tissues from HIV-1 patients, indicating clinical relevance of our findings. Fifth, administration of an engineered adeno-associated virus that uses the promoter of an inflammation-induced protein, endothelin-1 (AAV2/9-Endo-Glo1) to express Glo1 in hearts of Hu-NSG mice, attenuate coronary microvascular leakage, ischemia, fibrosis and myocardial dysfunction, establishing a cause-effect relationship between MG accumulation and myocardial dysfunction. This multi-PI project brings together the expertise of Drs. Keshore R. Bidasee (M-PI, heart failure) and Santhi Gorantla (M-PI, humanized mice and HIV-1 infection) and build on these findings to (1) delineate the pathobiological trajectories responsible for HIV-1 associated cardiac dysfunction in Hu-NSG mice in the absence and presence of cART; (2) delineate molecular mechanisms responsible for elevation of cardiac inflammation in cART-treated HIV-infected Hu-NSG mice and validate the findings in autopsied tissues from HIV-1 infected patients, and (3) investigate whether attenuating MG accumulation in HIV-infected and cART-treated Hu-NSG mice will blunt myocardial dysfunction. Accomplishments of these aims will not only define for the first time a novel link between inflammation and myocardial dysfunction in the setting of HIV-1 infection, but the data could pave the way for the development of urgently needed therapeutics to mitigate early onset myocardial dysfunction in PLWH.

摘要： 超过25%的中年HIV-1感染者（PLWH）有早发性心肌梗死， 疾病包括舒张功能障碍（DD）、症状性心力衰竭的先兆、呼吸困难、肺功能不全、 异常，频繁住院和心脏猝死。8 -16迄今为止， PLWH中的心肌功能障碍仍然知之甚少。缺乏信息和治疗 选项促使OAR将“预防和治疗艾滋病毒相关心脏病的策略”列为 艾滋病研究的优先领域。我们假设“PLWH的早发性心肌功能障碍是 由于细胞毒性糖酵解代谢产物甲基乙二醛（MG）的蓄积， 持续性心脏炎症”这一假设是基于最近获得的几条新证据 in our laboratories实验室.首先，使用人源化N 0 D/Scid-IL 2 Rg-/-（NSG）小鼠重建HIV-1感染的人源化N 0 D/Scid-IL 2 Rg-/-（NSG）小鼠。 免疫系统（Hu-NSG）发展为类似于患者中所见进行性心肌病。第二，cART 降低血浆HIV-1病毒血症，但不降低心脏炎症，这是由于 炎症生物标志物血管粘附蛋白-1（VAP-1）。第三，细胞毒性糖酵解副产物MG， 在有/无cART的HIV-1感染的Hu-NSG小鼠的心脏中积累，这是由于炎症诱导的 MG降解酶glycoproteinase-1（Glo 1）的下调。升高的MG在蛋白质上形成MG-H1加合物。 第四，在HIV-1尸检的心室组织中发现VAP-1和MG-H1增加，而Glo 1减少 患者，表明我们的研究结果的临床相关性。第五，施用工程腺相关病毒 使用炎症诱导蛋白内皮素-1（AAV 2/9-Endo-Glo 1）的启动子来表达 Hu-NSG小鼠心脏中的Glo 1，减轻冠状动脉微血管渗漏、缺血、纤维化和心肌梗死 功能障碍，建立MG蓄积和心肌功能障碍之间的因果关系。这 多PI项目汇集了Keshore R. Bidasee（M-PI，心力衰竭）和Santhi Gorantla (M-PI，人源化小鼠和HIV-1感染），并建立在这些发现（1）描绘的病理生物学 在不存在和存在的情况下，Hu-NSG小鼠中负责HIV-1相关心脏功能障碍的轨迹 （2）描述cART治疗的心脏炎症升高的分子机制。 HIV感染的Hu-NSG小鼠，并验证来自HIV-1感染患者的尸检组织中的发现，以及（3） 研究在HIV感染和cART治疗的Hu-NSG小鼠中减弱MG积累是否会钝化 心肌功能障碍这些目标的实现不仅将首次确定一种新的联系， 在HIV-1感染的情况下，炎症和心肌功能障碍，但这些数据可以为 开发迫切需要的治疗方法，以减轻PLWH中早发性心肌功能障碍。