Atazanavir is an antiretroviral medication used to treat and prevent HIV/AIDS, but its effects on cardiac fibrosis are unknown. The aim of this study was to determine the effects of atazanavir on myocardial infarction (MI)-induced cardiac fibrosis in rats and used a TLR 9 antagonist, hydroxychloroquine (HCQ) to elucidate the potential mechanism in vitro. The results indicated that atazanavir significantly attenuated CoCl2-induced neonatal rat cardiac fibroblast (rCFs) proliferation in a concentration-dependent manner. Treatment of rCFs with atazanavir 1-10 µM blocked CoCl2-induced nuclear factor kappaB phosphorylation (p-NF-κB), p-IκBα and high-mobility group box 1 (HMGB1) expression. Treatment of rCFs with atazanavir 3 µM blocked HMGB1 downstream, p-NF-κB by blocking HMGB1 binds to toll-like receptor 9 (TLR 9). Intragastric administration of atazanavir sulfate 30 mg/k ameliorated changes in the left ventricular systolic pressure (LVSP), + dp/dtmax, and - dp/dtmax after 4 weeks. This was associated with attenuation of α-SMA, HMGB1, p-NF-κB, TLR 9, collagen I, collagen III expression and hydroxyproline (Hyp) content in ischemic myocardial tissue. Additionally, continuous intragastric administration of atazanavir for 28 days attenuated cardiac remodeling. These data suggested that the protective effect of atazanavir is likely due to blocking of myocardial inflammatory cascades through an HMGB1/TLR 9 signaling pathway.
Keywords: Atazanavir; High mobility group box-1 protein; Myocardial infarction; Toll-like receptor 9.
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