The Inotropic Effect Of HIV Gp120 On Myocardium And Its Signaling Pathway

Recently, the diagnostic and therapeutic advances in AIDS have markedly improved the long-term survival of HIV-infected individuals. This improvement in prognosis has been accompanied by the recognition of other manifestations of HIV infection such as dementia and cardiomyopathy. The development of a cardiomyopathy is well-recongnized complication of HIV infection that results in a worse prognosis for those afflicted with AIDS. Mechanisms responsible for HIV cardiomyopathy are unknown, but they may include direct effects of HIV protein on the heart. Human Immunodeficiency Virus(HIV) envelope glycoprotein, gp120, which resides on the surface of the HIV virus, facilitates viral entry and invasion T cells. Evidence is accumulating that HIV gp120 may also play an important pathogenic role in HIV dementia and cardiomyopathy. This study aims to observate the effect of HIV gp120 on both in vitro cardiac myocytes and in vivo heart, and to analyse its signaling pathway for providing a novel therapeutic target for HIV as well as other cardiomyopathies.In vitro studies showed that adult rat ventricular myocyte(ARVM), continuously perfused with the HIV gp120(1μg/ml), resulted in biphasic inotropic effect: the initial 20min of positive inotropic effect corresponding ncrease in [Ca²⁺]_i, the following negative inotropic which persisted at least 2h without decrease in [Ca²⁺]_i and was blocked by p38MAP kinase inhibitor, SB203580. Western blot showed that exposure of AVRM to gp120 resulted in the phosphorylation of the upstream regulator of p38MAP kinase MKK3/6, p38MAK kinase itself, and its downstream effector, ATF-2, over a similar time course, and also phosphorylated troponin I. SB203580(5μM) selectively blocked gp 120 stimulated phosphorylation of MAPKAPK2,ATF-2,troponin I and did not block the phosphorylation of MKK3/6 or p38MAP kinase itself; Exposure of ARVM to gp120 also resulted in maximal activation of iPLA₂ by 60min as refected in hydrolysis of arachidonyl thiophatidylcholine that was completely blocked by iPLA₂ inhibitor, bromoenol lactone(BEL) or SB203580. The negative inotropic effect of gp120 was blocked by BEL, as well as SB203580. BEL did not block gp120-stimulated phosphorylation of p38MAPK itself, and/or its ownstream effectors, ATF2 or MAPKAPK2. However, BEL blockedgp 120-stimulated phosphorylation of troponin I.In vivo cardiac hemodynamic observation showed that a single injection of gp120 (50μg/kg) resulted in a specific decreased diastolic relaxation response to isoproterenol reflected in smaller LVP -dp/dtmin responses at 48 hrs followed by both systolic and diastolic dysfunction which persisted at least 12days in awake rats. Similarly instrumented, but vehicle injected rats maintained both systolic and diastolic function. Werstem blot shows that p38 MAP kinase in cardiac myocytes isolated from rats 48 hrs after the single injection of gp120 was phosphorylated.These results demonstrated that HIVgp120 induces cardiac dysfunction mediated by activation of p38MAP kinase-iPLA₂-troponin I signaling pathway, and directly contributes to HIV cardiomyopathy.