Glutathione Dependent and Independent Salutary Effects of NAC on HIV Tat Proteinopathy

Abstract

We have previously reported that cardiac myocyte‐specific expression of HIV‐Tat (Tat) results in a murine cardiomyopathy model. We now report that cardiac myocytes isolated from Tat exhibit decreased ATP (p<0.01; n=8–9) and GSH levels (p<0.01; n=8–9), decreased GSH/GSSG ratio (p<0.01; n=8–9), increased H2O2 (p<0.05; n=6) and catalase (p<0.05; n=6), and GPX1 (glutathione peroxidase 1) activities (p<0.05; n=6), blunted systolic function (%Fractional shortening, p<0.01; n=15; +dl/dt p<0.01; n=15) and diastolic function (‐dl/dt, p<0.01; n=15), and inotropic responses to Ca++ (p<0.01, n= 15) and shortened anatomical and functional survival in vitro (p<0.01, n=15). Treatment of Tat cardiac myocytes with the sulfhydryl donor, N‐acetylcysteine (NAC; 10−4 M) reversed both the positive and negative inotropic defects in Tat; increased GSH (p<0.01); GSH/GSSG (p<0.01); reversed H2O2 level (p<0.05) and GPX1 activity (p<0.05); normalized the blunted inotropic response to Ca2+ (p<0.01). In addition, NAC 10−7 M normalized duration of contractile function from <40 min to >120 min (p<0.01), while having no affect on GSH, GSH/GSSG. Elucidating molecular mechanisms involved in the GSH‐dependent and GSH‐independent salutary effects of NAC could identify novel therapeutic targets to mitigate the pathogenic effects of proteinopthies in cardiomyopathies and heart failure.