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.

Relationships Among HIV Infection, Metabolic Risk Factors, and Left Ventricular Structure and Function

“…Although not fully understood, it appears that HIV replication 16 may mediate impaired diastolic dysfunction through the viral glycoprotein 120 55,56 and the CXCR4-iPLA2-p38 mitogenactivated (MAP) kinase-troponin I inflammatory signaling pathway. [56][57][58] It is possible that peripheral metabolic complications and HIV may mediate diastolic dysfunction through a similar inflammatory pathway and therefore that is the reason we did not see an additive effect of metabolic complications with HIV in the current study. Metabolic syndrome is a proinflammatory state 59 and the MAP kinase pathway 60 and other G-protein-associated pathways 61 have been implicated in playing a role in non-HIV metabolic syndrome and CVD.…”

Diastolic dysfunction following HIV infection

“…In particular, p38 MAP kinase has been reported to regulate pathways involved in the Ser 23/24 phosphorylation of troponin I [15,16]. Interestingly, a direct correlation was reported between the attenuation of the lusitropic effect of isoproterenol by the p38 MAP kinase inhibitor with blocking the phosphorylation of both p38 MAP kinase and troponin I [14]. These data are most consistent with a selective effect of HIV gp120 on p38 MAP kinasetroponin I signaling that results in attenuated adrenergic enhancement of diastolic relaxation.…”

“…These clinical reports stimulated efforts to study the direct effects of recombinant HIV proteins in animal models to appreciate their potential pathogenic role in HIV cardiomyopathy [10][11][12][13][14][15]. The HIV coat protein, gp120, was reported to enhance IL-1beta-induced inducible nitric oxide synthase expression and nitric oxide production in neonatal rat cardiac myocytes in vitro [10].…”

“…A direct, negative inotropic effect of HIV gp120 on adult rat ventricular myocytes (ARVMs) was subsequently shown to be mediated through a novel CXCR4-iPLA2-p38 mitogen activated protein (MAP) kinase-troponin I signaling pathway [11][12][13]. Specifically relevant to Kelly et al was a report that the injection of HIV gp120 resulted in a selective defect in the diastolic relaxation (lusitropic) response to adrenergic stimulation in vivo [14]. Defective adrenergic signaling is a common characteristic of both ischemic and nonischemic cardiomyopathies [16].…”

Heart Failure in Patients With Human Immunodeficiency Virus Infection

“…51 This can result in increased myocardial expression of HLA class I antigens, which is seen more commonly in AIDS patients with symptomatic systolic dysfunction. 52 Interestingly, there is experimental evidence that blocking some of these proteins may be cardioprotective, 47, 51, 53, 54 and monthly intravenous immunoglobulin(s) in pediatric HIV-1 infected patients was shown to minimize left ventricular dysfunction and improve other markers of myocardial injury. 13, 30 …”