Transforming growth factor-β1-mediated cardiac fibrosis: potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease.
Review
Overview
abstract
HIV infection elevates the incidence of cardiovascular disease (CVD) independent of traditional risk factors. Autopsy series document cardiac inflammation and endomyocardial fibrosis in the HIV+ treatment naïve, and gadolinium enhancement magnetic resonance imaging has identified prominent myocardial fibrosis in the majority of HIV+ individuals despite use of suppressive antiretroviral therapies (ART). The extent of such disease may correlate with specific ART regimens. For example, HIV-infected patients receiving ritonavir (RTV)-boosted protease inhibitors have the highest prevalence of CVD, and RTV-exposed rodents exhibit cardiac dysfunction coupled with cardiac and vascular fibrosis, independent of RTV-mediated lipid alterations. We recently showed that platelet transforming growth factor (TGF)-β1 is a key contributor to cardiac fibrosis in murine models. We hypothesize that in the HIV+/ART naïve, cardiac fibrosis is a consequence of proinflammatory cytokine and/or ART-linked platelet activation with release of TGF-β1. Resultant TGF-β1/Smad signaling would promote collagen synthesis and organ fibrosis. We document these changes in a pilot immunohistochemical evaluation of cardiac tissue from two ART-naive pediatric AIDS patients. In terms of ART, we showed that RTV inhibits immunoproteasome degradation of TRAF6, a nuclear adapter signaling molecule critical to the regulation of proinflammatory cytokine signaling pathways involved in osteoclast differentiation and accelerated osteoporosis. We now present a model illustrating how RTV could similarly amplify TGF-β1 signaling in the promotion of cardiac fibrosis and accelerated CVD. Supportive clinical data correlate RTV use with elevation of NT-proBNP, a biomarker for CVD. We discuss potential interventions involving intrinsic modulators of inflammation and collagen degradation, including carbon monoxide-based therapeutics.
