Regulation of cardiac myocytes by HIV-1 gp 120

West Virginia University, Morgantown WV

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Abstract

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.