Regulation of cardiac myocytes by HIV-1 gp 120

HIV-1 gp 120 对心肌细胞的调节

• 批准号: 6496382
• 负责人: Mitchell Simon Finkel
• 金额: $ 18.25万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6496382
• 关键词: HIV envelope protein; HIV envelope protein gp120; adrenergic receptor; biological signal transduction; calcium channel; calcium ion; cardiac myocytes; heart ventricle; laboratory rat; mitogen activated protein kinase; muscle contraction; protein structure function; receptor expression; recombinant proteins; sarcolemma; tissue /cell culture

DESCRIPTION (provided by applicant): We will study myocardial dysfunction by studying the effects of recombinant HIV proteins on cardiac myocytes. We found that the envelope protein, gpl20, enhanced IL-I stimulated inducible nitric oxide synthase (iNOS; II) mRNA, protein and nitric oxide (NO)production by neonatal rat cardiac myocytes through a p38 kinase mediated mechanism. This initial observation in neonatal myocytes prompted us to explore direct inotropic effects of gpl20 on isolated adult rat ventricular myocytes (ARVM). Continuous infusion of ARVM with gpl20 significantly increased the percentage of fractional shortening (FS;function of contractility) in response to electrical field stimulation over 2 to 20 minutes with associated increase in [Ca++]i. Further, continuous perfusion of ARVM with gp120 resulted in frequent significant decrease in FS at 1 to 2 hrs that was not associated with any changes in [Ca++]i. Continuous perfusion of gpl20 was also associated with activation of p38 MAP kinase activity over 1 to 2 hours. Pre-treatment with the p38 MAP kinase inhibitor, SB 203580, resulted in persistence of the increased FS by gp120, while completely blocking the decrease in FS observed at 1-2 hours. This precedented biphasic effect on FS and [Ca++]i in ARVM by a single mediator supports the following hypothesis: HIV gpl20 regulates cardiac myocyte function through a novel signaling pathway. The owing Specific Aims will be pursued: (i) Elucidate the mechanisms involved in the initial positive inotropic effect of gp120. (ii) Elucidate the mechanisms involved in the delayed negative inotropic effect p120. (iii ) To identify and partially characterize a potentially novel receptor for HIV gp120 in ARVM. Clinical and biological relevance of these Specific Aims are underscored by the recent appreciation of important role that p38 MAP kinase plays in both cardiac adrenergic receptor signaling as well as ischemia-reperfusion that will be discussed later in this proposal.

描述（由申请人提供）：我们将通过 研究重组HIV蛋白对心肌细胞的影响。我们发现 包络蛋白GPL20增强了IL-I刺激诱导的一氮 氧化物合酶（iinos; ii）mRNA，蛋白质和一氧化氮（NO）生产 新生大鼠心脏肌细胞通过p38激酶介导的机制。这 新生儿肌细胞中的初步观察促使我们直接探索 GPL20对分离的成年大鼠心室肌细胞（ARVM）的肌力作用。 连续输注ARVM GPL20显着增加了百分比 响应 在2至20分钟以上的电场刺激，相关增加 [Ca ++] i。此外，使用GP120的ARVM连续灌注导致频繁 1至2小时的FS显着降低，与任何相关 [Ca ++] i的变化。 GPL20的连续灌注也与 p38 MAP激酶活性在1至2小时内的激活。与 p38 MAP激酶抑制剂，SB 203580，导致持续增加 fs by gp120，同时完全阻止了在1-2处观察到的FS的减少 小时。单个对fs和[Ca ++] i的先例二相影响。 介质支持以下假设：HIV GPL20调节心肌细胞 通过新型信号通路的功能。特定的目的将是 追捕：（i）阐明初始阳性涉及的机制 GP120的肌力作用。 （ii）阐明涉及的机制 延迟负性正性效应P120。 （iii）识别并部分 表征ARVM中HIV GP120的潜在新型受体。临床和 这些特定目标的生物学相关性被最近的 对p38 MAP激酶在两种心脏中发挥作用的重要作用的欣赏 肾上腺素能受体信号传导以及缺血 - 再灌注将是 在此提案的后面讨论。