Diastolic Heart Failure in HIV-1 infection

HIV-1 感染引起的舒张性心力衰竭

• 批准号: 10666630
• 负责人: KESHORE R BIDASEE
• 金额: $ 62.52万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666630
• 关键词: Anti-Retroviral Agents; Area; Arteriosclerosis; Attenuated; Autopsy; Biochemical; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cells; Chronic; Clinical; Coronary; Data; Development; Diabetes Mellitus; Diastolic heart failure; Disease; Endothelial Cells; Endothelium; Enzymes; Extravasation; Fibrosis; Fumarates; Functional disorder; Gene Transfer; Genus Hippocampus; Glycolysis; HIV; HIV Infections; HIV-1; Health Care Costs; Heart; Heart Diseases; Heart failure; Hemoglobin; Homeostasis; Hospitalization; Hospitals; Hypoxia; Hypoxia Inducible Factor; Impairment; Individual; Infection; Inflammation; Ischemia; Kinetics; Lactoylglutathione Lyase; Link; Lung; MAP Kinase Gene; Macrophage; Measures; Mediator; Modeling; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocarditis; Nitric Oxide; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Production; Publishing; Pulmonary Hypertension; Pyruvaldehyde; Recommendation; Regimen; Research; Smooth Muscle Myocytes; Sudden Death; Tenofovir; Therapeutic; Time; Tissues; Triose-Phosphate Isomerase; Up-Regulation; Viral; Viremia; Virus; Virus Replication; Visit; chrysin; cytotoxic; early onset; emtricitabine; humanized mouse; in vivo; inhibitor; innovation; mouse model; normal aging; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; pharmacologic; photoacoustic imaging; prevent; seropositive; sex; systemic inflammatory response; tool; transcription factor

Abstract: Contemporary estimates suggest that more than 40% of people living with chronic HIV-1 infection (PLWH) have diastolic heart failure (dHF), a harbinger for adverse clinical outcomes including pulmonary abnormalities, frequent hospitalizations, and sudden death. To date, the molecular causes for dHF 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 that “elevation of the cytotoxic glycolysis metabolite, methylglyoxal (MG) is a primary cause for dHF development in PLWH.” This elevation in MG is arising from HIV-1 induce upregulation of glycolysis in infected immunocytes followed by ischemia-induced increase in glycolysis in vascular cells and cardiac myocytes. 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) with assistance from Dr. Prasanta Dash (HIV-1 eradication and cardiovascular complications), to (1) Define pathobiological trajectories of dHF in relation to MG levels in HIV-1 infected Hu-mice with and with ARD treatment; (2) Characterize mechanisms by which MG increases in HIV-I infected immunocytes and in myocytes, macrophages and vascular cells under with and without ARD and hypoxia (3) Show that lowering MG will blunt dHF in HIV-infected Hu-mice with and without ARD. Accomplishments of these aims will not only define a novel link between glycolysis and early-onset dHF in the setting of HIV-1 infection, but the data could pave the way for the development of urgently needed therapeutics to mitigate this disease in PLWH.

抽象的： 目前的估计表明，超过 40% 的慢性 HIV-1 感染者 (PLWH) 舒张性心力衰竭（dHF），这是不良临床结果的先兆，包括肺部异常， 经常住院，甚至猝死。迄今为止，PLWH 中 dHF 的分子原因仍不清楚 明白了。由于信息匮乏和缺乏治疗方案，OAR 列出了“策略” 预防和治疗与艾滋病毒相关的心脏病”作为艾滋病毒研究的高度优先领域。我们假设 “细胞毒性糖酵解代谢物甲基乙二醛 (MG) 的升高是 dHF 的主要原因 PLWH 的发展。” MG 的升高是由于 HIV-1 诱导感染者糖酵解上调所致 免疫细胞随后缺血诱导血管细胞和心肌细胞糖酵解增加。这 多 PI 项目汇集了博士的专业知识。 Keshore R. Bidasee（M-PI，心力衰竭）和 Santhi Gorantla （M-PI、人源化小鼠和 HIV-1 感染）在 Prasanta Dash 博士的协助下（HIV-1 根除和 心血管并发症），以（1）定义与 HIV-1 中 MG 水平相关的 dHF 病理生物学轨迹 感染Hu-小鼠并接受ARD治疗； (2) 描述 HIV-I 中 MG 增加的机制 感染的免疫细胞以及肌细胞、巨噬细胞和血管细胞在有或没有 ARD 的情况下以及 缺氧 (3) 表明，在患有或不患有 ARD 的 HIV 感染 Hu 小鼠中，降低 MG 会减弱 dHF。 这些目标的实现不仅将定义糖酵解与早发性 dHF 之间的新联系 HIV-1 感染的背景，但这些数据可以为开发急需的治疗方法铺平道路 减轻 PLWH 中的这种疾病。

项目成果

HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2).

• DOI: 10.3390/ijms24010274
• 发表时间: 2022-12-23
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Alomar, Fadhel A.;Tian, Chengju;Bidasee, Sean R.;Venn, Zachary L.;Schroder, Evan;Palermo, Nicholas Y.;AlShabeeb, Mohammad;Edagwa, Benson J.;Payne, Jason J.;Bidasee, Keshore R.
• 通讯作者: Bidasee, Keshore R.