Atorvastatin suppresses HIV/antiretroviral drug-induced cardiac fibrosis and dysfunction in mice by blocking platelet TGFβ1 signaling.
Academic Article
Overview
abstract
Cardiovascular disease (CVD), both atherosclerosis-related and heart failure with preserved ejection fraction (HFpEF) linked to cardiac fibrosis, contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduces atherosclerotic CVD risk to a magnitude inconsistent with pitavastatin's impact solely on LDL-cholesterol and inflammation. We hypothesized that HFpEF in PWH is related to HIV-induced fibrosis mediated by platelet TGFβ1, is accelerated by certain contemporary ART, and may also be inhibited by statins. ART drugs used in REPRIEVE, including a nucleoside/nucleotide, integrase inhibitor-based regimen (tenofovir (TDF), emtricitabine (FTC), and dolutegravir (DTG)), and the protease inhibitors ritonavir (RTV) and darunavir (DRV), and the impact of atorvastatin, were examined in two HIV mouse models: transgenic HIV-Tg26 mice and HIV-PDX mice engrafted with T cells isolated from PWH. HIV-Tg26 and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV (p<0.05). Administration of TDF-FTC-DTG or RTV, but not DRV, resulted in a further ~2-fold increase in fibrosis (p<0.01). Cardiac fibrosis and intracardiac fat accumulation correlated with reduced diastolic function. Mice depleted of platelet TGFβ1 (TGFβ1Platelet-ΔTg26), or treated with atorvastatin, were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin effects were independent of changes in inflammatory cytokines. These effects correlated with reduced platelet activation and TGFβ signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. Our results indicate that certain ART regimens accelerate HIV-associated CVD characterized by HFpEF via platelet TGFβ1-dependent processes, which were mitigated by atorvastatin. We postulate that 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 TGFβ signaling.
