Diastolic Heart Failure in HIV-1 infection

摘要： 当代估计表明，超过40%的慢性HIV-1感染者（PLWH） 舒张性心力衰竭（dHF），包括肺部异常在内的不良临床结果的先兆， 频繁住院和猝死。迄今为止，PLWH中dHF的分子原因仍然很差 明白信息的缺乏和治疗方案的缺乏促使OAR列出了“策略 预防和治疗艾滋病毒相关的心脏病”作为艾滋病毒研究的优先领域。我们假设 细胞毒性糖酵解代谢物甲基乙二醛（MG）升高是dHF的主要原因 在PLWH的发展”。MG的这种升高是由HIV-1诱导感染者糖酵解上调引起的。 免疫细胞中的糖酵解增加，随后缺血诱导的血管细胞和心肌细胞中的糖酵解增加。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）与Prasanta Dash博士的协助（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 感染的Hu-小鼠和ARD治疗;（2）表征HIV-I中MG增加的机制 感染的免疫细胞和在有和没有ARD下的肌细胞、巨噬细胞和血管细胞中， 缺氧（3）表明降低MG将减弱有和无ARD的HIV感染的Hu小鼠中的dHF。 这些目标的实现不仅将确定糖酵解和早发性dHF之间的新联系， HIV-1感染的背景，但这些数据可以为开发迫切需要的治疗方法铺平道路 来减轻艾滋病病毒携带者的病情。

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.