Abstract 432: Rapamycin Can Ameliorate Antiretroviral Drug Mediated Cardiotoxicity

Abstract

Introduction: In current therapy, due to application of combined antiretroviral drugs (cART), HIV related mortality significantly reduced, and AIDS became a chronic disease. Although, cART treatment increases life expectancy of AIDS patients, growing AIDS population suffer due to several organ diseases and heart failure is one of the leading causes of comorbidity and mortality. Hypothesis: We tested the hypothesis that application of cART induces cardiotoxicity through inhibition of cellular protein quality control (PQC) and dysregulation of mitochondrial function. Method and results: Cellular protein quality control was analyzed using cardiac tissue samples from HIV+ patients treated with cART and healthy donors. Western blot shows that there is upregulation of autophagy marker protein LC3 II in ART treated heart compared to healthy donor. Additionally, we found that there are abnormalities in the mitochondrial oxidative phosphorylation complexes (OXOPHOS) in the ART treated patient’s heart, compared to healthy donor heart. Using neonatal rat ventricular cardiomyocytes, we tested the role of ART in cellular PQC and mitochondrial function. Our data shows that cardiomyocytes treated with the cART (Ritonavir+ Atazanavir+ abacavir+ Lamivudine) have increased expression of autophagy proteins LC3 II and P62 and higher level of pELF2α. These suggest that, the cardiomyocytes treated with ART have dysregulation of autophagy and increased ER stress. Further, we found that cardiomyocytes treated with cART have high level of mitochondrial superoxide and decreased mitochondrial membrane potential. Mitochondrial function detected in whole cells shows that in ART treated cardiomyocytes there is significantly low OCR compared to control cells. Interestingly, application of pharmacological drug rapamycin can improve the cellular PQC and mitochondrial function in ART treated cells. Conclusion: ART treatment induces cardiotoxicity through inhibition of cellular PQC and dysregulation of mitochondrial function and rapamycin might be important therapeutic drug to reduce the ART mediated cardiotoxicity.