N-acetylcysteine reverses cardiac myocyte dysfunction in HIV-Tat proteinopathy.

Abstract

HIV cardiomyopathy remains highly prevalent among the estimated 33 million HIV-infected individuals worldwide. This is particularly true in developing countries. Potential mechanisms responsible for myocardial dysfunction following HIV infection include direct effects of HIV proteins. We have previously reported that cardiac myocyte-specific expression of HIV-Tat (Tat) results in a murine cardiomyopathy model. We now report that Tat exhibits decreased myocardial ATP [wild type (WT) vs. Tat transgenic (TG), P < 0.01] and myocyte GSH levels (WT vs. TG, P < 0.01), decreased GSH/GSSG ratio (WT vs. TG, P < 0.01), increased H(2)O(2) levels (WT vs. TG, P < 0.05), and increased catalase (TG vs. WT, P < 0.05) and GPX1 (glutathione peroxidase 1) activities (WT vs. TG, P < 0.05), blunted cardiac myocyte positive inotropy (% peak shortening, WT vs. TG, P < 0.01; +dl/dt, WT vs. TG, P < 0.01) and negative inotropy (-dl/dt, WT vs. TG, P < 0.01), and blunted inotropic responses to Ca(2+) (P < 0.01, for each) and shortened anatomical and functional survival in vitro (P < 0.01). The sulfhydryl donor, N-acetylcysteine (NAC; 10(-4) M), completely reversed both the positive and negative inotropic defects in Tat; increased GSH (P < 0.01) and GSH/GSSG (P < 0.01); reversed H(2)O(2) level (P < 0.05) and GPX1 activity (P < 0.05); and normalized the blunted inotropic response to Ca(2+) (P < 0.01). NAC (10(-7)) M normalized duration of contractile function from <40 min to >120 min (P < 0.01), with no effect on GSH and GSH/GSSG. NAC (10(-4) M) reverses cardiac myocyte dysfunction and markers of oxidative stress. NAC (10(-7) M) enhances myocyte function independent of changes in glutathione. Elucidating the molecular mechanisms involved in the GSH-dependent and GSH-independent salutary effects of NAC should identify novel therapeutic targets for myocardial proteinopathies recently appreciated in human cardiomyopathies.

• Authors: Fangping Chen, William Lewis, John M Hollander, Walter Baseler, Mitchell S Finkel
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 113 Issue 1 Pg. 105-13 (Jul 2012) ISSN: 1522-1601 [Electronic] United States
• PMID: 22556393 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Gene Products, tat
• Adenosine Triphosphate
• Hydrogen Peroxide
• Catalase
• Glutathione Peroxidase
• Glutathione
• Calcium
• Acetylcysteine
• Glutathione Peroxidase GPX1
• Gpx1 protein, mouse

Topics

• Acetylcysteine (therapeutic use)
• Adenosine Triphosphate (analysis)
• Animals
• Antiviral Agents (therapeutic use)
• Calcium (pharmacology)
• Cardiomyopathies (drug therapy, metabolism, virology)
• Catalase (analysis)
• Female
• Gene Products, tat (metabolism)
• Glutathione (analysis)
• Glutathione Peroxidase (analysis)
• HIV Infections (complications, metabolism)
• Hydrogen Peroxide (analysis)
• Male
• Mice
• Mice, Transgenic
• Myocardial Contraction (drug effects, physiology)
• Myocytes, Cardiac (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Glutathione Peroxidase GPX1