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.
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.
Background: Daunorubicin (DNR)-induced cardiotoxicity, which is closely associated with cardiomyocyte apoptosis, limits the drug's clinical application. The activation of the extracellular regulated protein kinases (ERKs) pathway is responsible for the pro-apoptosis effect of DNR Sodium ferulate (SF) has recently been found to attenuate both DNR-induced cardiotoxicity and mitochondrial apoptosis in juvenile rats. Nonetheless, the precise mechanism underlying SF-induced cardio-protection remains unclear. Methods: The DNR-injured H9c2 cell model was prepared by incubating the cells in 1 µM DNR for 24 h. Amounts of 15.6, 31.3 or 62.5 µM SF were simultaneously added to the cells. The effect of SF on the cytotoxic and apoptotic parameters of the cells was studied by monitoring apoptosis regulation via the ERKs pathway. Results: SF attenuated DNR-induced cell death (particularly apoptotic death), cTnI and β-tubulin degradation, and cellular morphological changes. SF reduced mitochondrial membrane potential depolarization, cytochrome c leakage, and caspase-9 and caspase-3 activation. SF also decreased ERK1/2, phospho-ERK1/2, p53 and Bax expression and increased Bcl-2 expression. These effects were similar to the results observed when using the pharmacological ERKs phosphorylation inhibitor, AZD6244. Conclusion: We determined that SF protects H9c2 cells from DNR-induced apoptosis through a mechanism that involves the interruption of the ERKs signaling pathway.
Chronic, excessive alcohol consumption is associated with myocardial dysfunction in humans. The molecular mechanisms and cellular signaling pathways contributing to this cardiac dysfunction remain largely unknown. This study examined the effects of chronic alcohol consumption on myocardial function and cardiac myocyte signaling pathways. Adult male rats were fed a commercially prepared diet containing either ethanol (13 g/kg/d) or isocaloric control diet for 1 month. In vivo hemodynamics were measured in awake rats after inserting a catheter tip in the left ventricle under general anesthesia. Ventricular dysfunction was evidenced in awake, alcohol-fed rats by increased left ventricular end diastolic pressure, decreased systolic developed left ventricular pressure, and decreases in both positive and negative dp/dt compared with controls. Cardiac myocytes isolated from alcohol-fed rats also demonstrated an attenuated response to the beta-adrenergic agonist, isoproterenol, compared to controls. This response was significantly reversed by the nitric oxide synthase (NOS) inhibitor, N-monomethyl-L-arginine (L-NMMA). Western analyses confirmed inducible nitric oxide synthase (iNOS) protein synthesis in cardiac myocytes isolated from alcohol fed rats. It is therefore concluded that chronic alcohol ingestion results in iNOS-mediated attenuation of adrenergic signaling and depression in both systolic and diastolic function in rats.
Daunorubicin (DNR) is a widely used chemotherapeutic agent; however, its clinical use is limited because of its cardiotoxicity. This study was aimed to investigate the protective effect of sodium ferulate (SF), an effective component from traditional Chinese herbs, against DNR-induced cardiotoxicity in juvenile rats. DNR was administered intraperitoneally to rats at the dosage of 2.5 mg·kg(-1)·wk(-1) for 5 consecutive weeks (cumulative dose of 12.5 mg/kg) or in combination with intraperitoneal injection of SF at 50 mg·kg(-1)·d(-1) over a period of 30 days. The animals were killed 6 days after the last injection of DNR. SF significantly ameliorated the DNR-induced cardiac dysfunction, structural damage of the myocardium, and release of lactate dehydrogenase and creatine kinase. Treatment with SF also reversed DNR-induced oxidative stress as evidenced by a decrease in malondialdehyde levels with a concomitant increase in myocardical superoxide dismutase activities. Furthermore, SF afforded significant cardioprotection against DNR-induced apoptosis in vivo and effectively suppressed the complex mitochondrion-dependent apoptotic signaling triggered by DNR. This study indicates that SF may improve cardiac function by inhibition of oxidative stress and apoptosis, thus providing a beneficial effect on the prevention of DNR-induced cardiotoxicity.
<b><i>Background:</i></b> Effective antiretroviral therapy extends the survival of patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome, but these patients remain at higher risk for heart diseases compared with the general population. Previous studies have suggested that HIV-1 glycoprotein 120 (gp120) may be associated with heart disease. However, the underlying mechanisms by which HIV-1 gp120-mediated myocardial injury occurs remain unknown. <b><i>Objective:</i></b> The current study aimed to uncover the mechanism of C-C chemokine receptor 5 (CCR5) coreceptor (R5) HIV-1 gp120-induced myocardial injury. <b><i>Methods:</i></b> Morphology analysis, determination of the percentage of cell apoptosis, as well as lactate dehydrogenase (LDH) and creatine kinase (CK) assays were used to analyze whether R5 HIV-1 gp120 induced myocardial cell injury. We analyzed the phosphorylation of p38 mitogen-activated protein kinase (MAPK) with the CCR5 antagonist D-Ala-peptide T-amide (DAPTA) and NMDA receptor antagonist MK801, detected LDH and CK assays with p38 MAPK antagonist SB203580 (SB), and detected the percentage of cell apoptosis and death with DAPTA to investigate the mechanism of R5 HIV-1 gp120-induced myocardial cell injury. <b><i>Results:</i></b> R5 HIV-1 gp120 damaged myocardial cells and induced p38 MAPK phosphorylation. SB blocked R5 HIV-1 gp120-induced myocardial cell injury. DAPTA blocked R5 HIV-1 gp120-mediated p38 MAPK phosphorylation, while MK801 did not. DAPTA inhibited R5 HIV-1 gp120-induced myocardial cell injury. <b><i>Conclusion:</i></b> Our data indicate that R5 HIV-1 gp120 activated p38 MAPK to trigger myocardial cell injury by the CCR5 coreceptor.
Mechanisms responsible for HIV cardiomyopathy are unknown, but may include direct effects of HIV proteins on the heart. Transgenic mice overexpressing HIV Tat protein targeted to the myocardium, +/−Tat high transgenic mice (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 were measured in awake mice after inserting a catheter tip in the left ventricle under general anesthesia. Under the age of three month, the heart rate (HR) was significantly lower in TG (591¡À47 vs 716¡À45 bpm, TG vs Control, 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 Control. At 6 mos, however, ventricular dysfunction was evidenced in TG (HR = 580¡À47 vs 673¡À25 bpm, TG vs Control, p<0.05); LVSP (132¡À6 mmhg vs 147¡À6 mmhg, TG vs Control; p<0.05); LVEDP (15¡À4 mmhg vs 8¡À6 mmhg, TG vs Control, p<0.05); +dp/dt= 8872¡À331 mmhg/s vs 10026¡À796 mmhg/s TG vs Control, p<0.01) and .Cdp/dt (7403¡À432 mmhg/s vs 8835¡À368 mmhg/s, TG vs Control, p<0.01; n=8–12 in each group). Thus, targeted myocardial transgenic expression of HIV Tat results in depression in both systolic and diastolic function in mice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.