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

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

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

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Figure 1

Effect of ART on cardiac fibrosis in HIV mice.

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Effect of ART on cardiac fibrosis in HIV mice. (A) Representative images...
(A) Representative images of Masson’s trichome staining of heart sections from FVB/NJ -No HIV controls, HIV-Tg26 mice, and HIV-Tg26 mice treated with ART ritonavir (RTV), darunavir (DRV), or the tenofovir-emtricitabine-dolutegravir (TDF-FTC-DTG) cocktail (TDFc) for 8 weeks. Excessive collagen is indicated in blue. (B) Representative images of Picrosirius red staining, showing fibrotic areas as a mixture of green, red, and yellow, under polarized light microscopy. (C) Representative images of Masson’s trichome staining of heart sections from NSG controls, HIV-infected (HIV-PDX) mice, and HIV-PDX mice treated with TDFc for 8 weeks. (D) Quantification of fibrotic areas in Masson’s trichome–stained and Picrosirius red images showed that HIV-infected mice had higher cardiac fibrosis than controls. ART-treated HIV-Tg26 mice, with the exception of those treated with DRV, had more fibrotic areas than untreated ones. (E) Blind scoring for fibrosis by microscopy on a 0–4 scale showed that ART-treated mice exhibited higher perivascular and interstitial fibrosis than untreated HIV-PDX control mice. Both patterns of fibrosis were quantified from whole-heart Masson’s trichome–stained and Picrosirius red images acquired from a slide scanner (Supplemental Figures 1, A–C). In D and E, total, perivascular, and interstitial fibrosis were quantified using the algorithm shown in Supplemental Figure 1A or blindly by a pathologist and a trained technician who were unaware of mouse genotype. Each dot in the bar graphs represents an individual mouse; data are presented as mean ± SD; P values < 0.05 were considered significant using standard 2-tailed Student’s t test.