Regulation of cardiac myocytes by HIV-gp120

HIV-gp120 对心肌细胞的调节

• 批准号: 7436300
• 负责人: Mitchell Simon Finkel
• 金额: $ 27.28万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436300
• 关键词: Adult; CXCR4 Receptors; Calcium; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Catheters; Clinical Trials; Collaborations; Complement; Data; Depressed mood; Dilated Cardiomyopathy; Doctor of Philosophy; Echocardiography; Etiology; Frequencies; Functional disorder; Funding; Future; HIV; HIV Envelope Protein gp120; Human; In Vitro; Individual; Injection of therapeutic agent; Lead; Mediating; Messenger RNA; Modeling; Monitor; Muscle Cells; Myocardial dysfunction; Neonatal; Patients; Phosphorylation; Production; Proteins; Rattus; Recombinants; Regulation; Reporting; Research Training; Role; Series; Signal Pathway; Switzerland; Techniques; Time; Training; Travel; Troponin I; Ventricular; awake; base; clinically relevant; day; design; hemodynamics; human MAPK14 protein; in vivo; insight; intravenous injection; mitogen-activated protein kinase p38; novel; papillary muscle

DESCRIPTION (provided by applicant): Diastolic dysfunction followed by systolic dysfunction leading to dilated cardiomyopathy (DCM) has been documented with surprisingly high frequency in HIV infected individuals. The pathophysiologic mechanisms responsible for HIV DCM are not well understood. We received 3 years of initial RO-1 funding to clarify the potential direct contribution of HIV to myocardial dysfunction by studying the effects of the recombinant HIV envelope glycoprotein, gp120, on adult rat ventricular myocytes (ARVM). Reviewers of our previous renewal application raised concerns about the clinical relevance of the short-term effects of gp120 on ARVM in vitro. Accordingly, the Co-PI (Hong Kan, MD, PhD) traveled to Lausanne, Switzerland to receive advanced training in sophisticated in vivo techniques in awake rats through a collaboration with the Swiss Cardiovascular Research and Training Network (SUK). We now report: (1) diastolic dysfunction in vivo 48 hrs following intravenous injection of HIV gp120 associated with (2) p38 MAP kinase activation and (3) iNOS protein and followed by (4) systolic and (5) diastolic dysfunction in vivo for at least 12 days following iv injection of gp120. These data complement the novel results of our initial 3 yrs of RO-1 funding to study the negative inotropic effect of gp120 on ARVM mediated through a novel CXCR4-p38MAPkinase-iPLA2-froponin I signaling pathway that supports our initial hypothesis: HIV gp120 regulates cardiac myocyte function through a novel signaling pathway. However, our new Specific Aims focus on more clinically relevant in vivo and ex vivo approaches: (I) Establish the time course of the effects of intravenous injection of HIV gp120 on cardiac systolic and diastolic function in vivo using catheter-based hemodynamic monitoring and echocardiography. (II) Determine the effects of intravenous injection of HIV gp120 on isolated adult rat ventricular myocyte (ARVM) and papillary muscle systolic arid diastolic function. (Ill) Elucidate the signaling pathways involved in the systolic and diastolic effects of intravenous injection of HIV gp120 on adult rat ventricular myocytes (ARVM). The successful completion of these Specific Aims will provide the insights necessary to perform focused interventional studies in this newly identified HIV cardiomyopathy model and potentially lead to clinical trials in humans with HIV cardiomyopathy.

描述（由申请人提供）：舒张功能障碍随后发生了收缩功能障碍，导致扩张心肌病（DCM）已记录在HIV感染的个体中的出人意料高频。对HIV DCM负责的病理生理机制尚不清楚。我们通过研究重组HIV HIV包膜糖蛋白GP120对成年大鼠心室心肌细胞（ARVM）的影响，通过研究HIV对心肌功能障碍的潜在直接贡献，以阐明HIV对心肌功能障碍的潜在直接贡献。我们先前续签应用的审稿人对GP120对ARVM体外的短期影响的临床相关性引起了人们的关注。因此，通过与瑞士心脏血管研究和培训网络（SUK）的合作，Co-Pi（Hong Kan，MD，PhD）前往瑞士洛桑，在醒着老鼠的体内技术进行了先进的体内技术培训。我们现在报告：（1）静脉注射HIV GP120后48小时的舒张功能障碍与（2）P38 MAP MAP激酶激活和（3）Inos蛋白，然后（4）收缩期和（5）舒张功能障碍在Vivo中至少在Vivo中至少在Vivo中iv iv Gp120 iv gp120。这些数据补充了我们最初3年RO-1资金的新结果，以研究GP120对通过新型CXCR4-P38Mapkinase-ipla2-Fropoonin I信号通路介导的ARVM的负面肌力效应，从而支持我们的最初假设：HIV GP120通过新颖的信号途径调节心脏肌细胞函数。但是，我们的新特定目的集中在体内和体内方法上更临床相关的方法：（i）使用基于导管的血液动力学监测和超声心动图建立静脉注射HIV GP120对心脏收缩和舒张功能的影响。 （ii）确定HIV GP120静脉注射对分离的成年大鼠心室心肌（ARVM）和乳头状肌肉收缩压干燥舒张功能的影响。 （病）阐明了HIV GP120对成年大鼠心室心肌细胞（ARVM）静脉注射HIV GP120的收缩和舒张作用所涉及的信号传导途径。这些特定目标的成功完成将提供在这种新发现的HIV心肌病模型中进行重点介入研究所需的见解，并有可能导致患有HIV心肌病的人的临床试验。