p38 MAP kinase inhibitor prevents diastolic dysfunction in rats following HIV gp120 injection in vivo

Abstract

HIV infection in patients is associated with a surprisingly high frequency of diastolic dysfunction followed by the development of a dilated cardiomyopathy. Potential mechanisms include direct effects of HIV proteins, including gp120. We have previously reported direct inotropic and p38 MAP kinase signaling effects of HIV gp120 on isolated cardiac myocytes in vitro. We now report effects of a single injection of HIV gp120 on cardiac hemodynamics in vivo. HIV gp120 (50 microg/kg) was injected intravenously and hemodynamics assessed at 1, 24, 48 and 72 h in freely ambulatory, awake rats. Rats injected with gp120 demonstrated a blunted diastolic response to increasing intravenous (IV) injections of the beta-adrenergic agonist, isoproterenol (ISO), compared with similarly instrumented controls at 48 h (gp120 vs. control, P < 0.01; n = 6, for each). Pre-treatment with the p38 MAP kinase inhibitor, SB 203580, prevented the diastolic dysfunction (gp120 + SB vs. control, P = NS; n = 6, for each). Hemodynamic changes correlated with inhibition of both p38 MAP kinase and troponin I phosphorylation by SB in vivo. There were no differences in ISO dose-response curves between gp120-treated and control rats at 1, 24 or 72 h (P = NS; n = 6, for each). Thus, evidence of diastolic dysfunction is apparent in vivo in rats following a single dose of HIV gp120. To our knowledge, this is the first report of a hemodynamic effect of an HIV protein in vivo. These findings lend further support to the hypothesis that the HIV virus, itself, may contribute to myocardial dysfunction in patients infected with HIV via a p38 MAP kinase mechanism.