Exposure of adult rat ventricular myocytes to HIV gp120 caused a delayed negative inotropic effect that was blocked by the p38 MAP kinase inhibitor SB-203580.
HIV gp120 induces a delayed negative inotropic effect in adult rat ventricular myocytes mediated by p38 MAP kinase activation, suggesting a mechanism for HIV-associated cardiomyopathy.
Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca2+ concentration (Ca2+i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased Ca2+i within 5 min and then depressed FS without a decrease in Ca2+i by 20-60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 microM) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 microM) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 microM) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.
Kan et al. (Thu,) conducted a other in HIV-associated myocardial dysfunction. HIV gp120 and SB-203580 was evaluated on Percent fractional shortening (FS) and intracellular ionized free Ca2+ concentration. Exposure of adult rat ventricular myocytes to HIV gp120 caused a delayed negative inotropic effect that was blocked by the p38 MAP kinase inhibitor SB-203580.
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