HIV Type 1 Glycoprotein 120 Inhibits Cardiac Myocyte Contraction

Chen, Fuhua; Shannon, Kevin; Ding, Shulan; Silva, Monica E.; Wetzel, Glenn T.; Klitzner, Thomas S.; Krogstad, Paul

doi:10.1089/08892220260139512

Cited by 24 publications

(12 citation statements)

References 25 publications

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“…This observation argues against a productive infection of cardiomyocytes by HIV-1 as a primary mechanism of HIVCM, as previously proposed (4). Instead, it suggests that indirect mechanisms initiated by inflammatory cells are plausible, such as secretion of cytokines, in particular tumor necrosis factor-␣ (TNF-␣) (5), nitric oxide (6,7), and viral proteins, in particular gp120 (7,8) and Tat (9). In agreement with an indirect model, transgenic mice expressing the entire HIV-1 coding sequences in T cells and monocyte͞macrophages developed a multitude of complications (10), including multifocal cardiomyopathy (P. Jolicoeur, personal communication), which were found to be related to Nef expression (11).…”

mentioning

confidence: 77%

Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

Twu

Liu

Popik

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

100

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We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-␣. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-␣ and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1-or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOP-RANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion-and death receptor-controlled apoptotic pathways.

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mentioning

confidence: 77%

Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

Twu

Liu

Popik

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

100

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“…In addition, HIV gp120 has been reported to activate apoptotic signaling pathways in cardiac myocytes [41] and inhibit field-stimulated contractions and L-type Ca 2? currents in rabbit ventricular myocytes [43]. A cardiomyopathy observed in a murine model of AIDS has been associated with increased cardiac protein nitration, rather than immune-mediated damage [44].…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

et al. 2008

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The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.

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“…We and others have explored the direct effects of recombinant HIV proteins in animal models in an effort to appreciate their potential pathogenic role in HIV-infected patients [12][13][14][15][16]. Another approach for studying the direct effects of HIV proteins has been to study the effects of the introduction of HIV genes into transgenic animal models [17].…”

Section: Introductionmentioning

confidence: 99%

Dilated Cardiomyopathy in Transgenic Mice Expressing HIV Tat

et al. 2009

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Mechanisms responsible for HIV cardiomyopathy are unknown, but may include direct effects of HIV proteins on the heart. Transgenic mice (TG) expressing HIV Tat protein targeted to the myocardium, +/- Tat TG, have revealed anatomical and biochemical defects in the heart. The present studies were conducted to clarify the effect of Tat on cardiac function. In vivo hemodynamics was measured in awake mice after inserting a catheter tip in the left ventricle under general anesthesia. Under the age of 3 months, the heart rate (HR) was significantly lower in TG (591 +/- 47 vs. 716 +/- 45 bpm, TG versus FVB control (FVB), respectively (P < 0.05; n = 8-12). Other hemodynamic indexes, including left ventricular systolic pressure (LVSP), positive and negative dp/dt (mmHg/s), and left ventricular end diastolic pressure (LVEDP) remained indistinguishable from FVB. At 6 months, however, ventricular dysfunction was evident in TG (HR = 580 +/- 47 vs. 673 +/- 25 bpm, TG versus FVB, P < 0.05); LVSP (132 +/- 6 vs. 147 +/- 6 mmHg, TG versus FVB; P < 0.05); LVEDP (15 +/- 4 vs. 8 +/- 6 mmHg, TG vs. FVB, P < 0.05); +dp/dt = 8872 +/- 331 vs. 10026 +/- 796 mmHg/s TG versus FVB, P < 0.01) and -dp/dt (7403 +/- 432 vs. 8835 +/- 368 mmHg/s, TG versus FVB, P < 0.01; n = 8-12, in each group). The change in percentage of fractional shortening in response to isoproterenol was also significantly reduced in cardiac myocytes isolated from TG versus FVB (P < 0.05). Thus, targeted myocardial transgenic expression of HIV Tat in mice results in relative bradycardia, depression in systolic and diastolic functions in vivo, and blunted adrenergic responsiveness in vitro.

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HIV Type 1 Glycoprotein 120 Inhibits Cardiac Myocyte Contraction

Cited by 24 publications

References 25 publications

Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

CXCR4 Receptor Antagonist Blocks Cardiac Myocyte P38 MAP Kinase Phosphorylation by HIV gp120

Dilated Cardiomyopathy in Transgenic Mice Expressing HIV Tat

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