Atorvastatin suppresses HIV/antiretroviral drug–induced cardiac fibrosis and dysfunction in mice by blocking platelet TGF-β1 signaling

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Abstract

Cardiovascular disease (CVD) contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduced atherosclerotic CVD risk to a magnitude inconsistent with pitavastatin’s impact solely on LDL cholesterol and inflammation. Here, atorvastatin and ART used in REPRIEVE, including tenofovir, emtricitabine, and dolutegravir, ritonavir and darunavir were examined in 2 mouse models: transgenic HIV-Tg26 mice and HIV-PDX mice engrafted with T cells from PWH. HIV-Tg26 and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV. Administration of tenofovir, emtricitabine, and dolutegravir or ritonavir, but not darunavir, resulted in an approximately 2-fold increase in fibrosis. Mice depleted of platelet TGF-β1 or treated with atorvastatin were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin’s effects were independent of changes in inflammatory cytokines, which correlated with reduced platelet activation and TGF-β signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. Our results indicate that certain ART regimens accelerate HIV-associated CVD characterized by heart failure with preserved ejection fraction via platelet TGF-β1–dependent processes, which were mitigated by atorvastatin. Our findings provide a potential mechanism for the pleiotropic effects of statins in HIV/ART-linked CVD, which could be targeted by antiplatelet agents or inhibition of TGF-β signaling.

Authors

Kumar Subramani, Denys Babii, Brienne Cole, Tayyab A. Afzal, Thamizhiniyan Venkatesan, Trevor Word, Sandra Gostynska, Sixia Chen, Kar-Ming Fung, Ali Danesh, Itzayana G. Miller, Paul Klotman, Brad R. Jones, Jeffrey Laurence, Jasimuddin Ahamed