iPLA2 inhibitor blocks negative inotropic effect of HIV gp120 on cardiac myocytes

Author(s): Kan H, Xie Z, Finkel MS


Recent improvements in survival from AIDS have been accompanied by an increased recognition of the potential importance of other manifestations of HIV infection, including cardiomyopathy. Mechanisms responsible for HIV cardiomyopathy are unknown, but may include direct effects of HIV proteins on the heart. We previously provided support for direct effects of HIV proteins by demonstrating a negative inotropic effect of the HIV coat protein, gp120, on isolated adult rat ventricular myocytes (ARVM). We now report that this negative inotropic effect of HIV gp120 is mediated by a signaling pathway involving p38 MAP kinase, iPLA2 and troponin I. Exposure of ARVM to HIV gp120 resulted in maximal activation of iPLA2 by 60 min as reflected in hydrolysis of arachidonyl thiophosphatidylcholine that was completely blocked by the iPLA2 inhibitor, bromoenol lactone (BEL) or the p38 MAP kinase inhibitor, SB203580. The negative inotropic effect of gp120 was blocked by BEL, as well as SB203580. BEL did not block gp120 stimulated phosphorylation of p38 MAP kinase itself, and/or its downstream effectors, ATF2 or MAPKAP2. However, BEL did block gp120-stimulated phosphorylation of troponin I. Thus, the negative inotropic effect of HIV gp120 requires activation of p38 MAP kinase and iPLA2; as well as troponin I phosphorylation. Activation of this novel p38 MAP kinase-iPLA2-troponin I signaling pathway may contribute to HIV cardiomyopathy.

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