Diastolic Heart Failure in HIV-1 infection

摘要： 当代的估计表明，超过40%的慢性HIV-1感染者(PLWH)患有 舒张性心力衰竭(DHF)是包括肺异常在内的不良临床结果的先兆， 频繁住院和猝死。到目前为止，PLWH中DHF的分子病因仍然很少。 明白了。这种信息的匮乏和治疗选择的缺乏促使OAR列出了 预防和治疗艾滋病毒相关心脏病“是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产物甲基乙二醛(MG)升高是DHF的主要原因 在PLWH方面的发展。MG的这种升高是由于HIV-1诱导感染患者糖酵解上调所致 免疫细胞在缺血后引起血管细胞和心肌细胞糖酵解增加。这 多重PI项目汇集了Keshore R.Bidasee博士(M-PI，心力衰竭)和Santhi Gorantla博士的专业知识 (M-PI、人源化小鼠和艾滋病毒-1感染)，由Prasanta Dash博士协助(根除艾滋病毒-1和 心血管并发症)，以(1)确定DHF的病理生物学轨迹与HIV-1中MG水平的关系 感染HU-小鼠和ARD治疗；(2)表征MG增加HIV-I的机制 感染的免疫细胞和肌细胞、巨噬细胞和血管细胞在有或没有ARD和 低氧(3)表明降低MG可钝化伴有和不伴有ARD的HIV感染HU小鼠的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，但这些数据可能为开发急需的治疗方法铺平道路 以减轻PLWH中的这种疾病。

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.