Significance of hypoxia-inducible factor-1α expression with atrial fibrosis in rats induced with isoproterenol

Abstract

Atrial interstitial fibrosis plays a dual role in inducing and maintaining atrial fibrillation (AF). Hypoxia-inducible factor-1α (HIF-1α) has been reported as closely associated with renal, liver and pulmonary fibrosis diseases. However, whether HIF-1α is involved in myocardial fibrosis, and the associations between HIF-1α, transforming growth factor-β₁ (TGF-β₁) and matrix metalloproteinase-9 (MMP-9) remain unknown. Therefore, this area warrants studying for the significance of AF diagnosis and treatment. The present study investigated the expression of HIF-1α in atrial fibrosis and its possible mechanism in isoproterenol (ISO)-induced rats. The three groups of rats; control, ISO and ISO plus sirolimus [also known as rapamycin (Rapa)], were treated for 15 days and sacrificed to remove the myocardial tissues. The expression levels of HIF-1α, TGF-β₁ and MMP-9 and their associations with atrial fibrosis were examined through histomorphology and protein and mRNA levels. The protein and mRNA levels of HIF-1α, TGF-β₁ and MMP-9 in the ISO group were increased markedly (P<0.01) compared with the control group, while those in the Rapa group were clearly decreased (P<0.01) compared with the ISO group. The protein and mRNA levels of HIF-1α, TGF-β₁ and MMP-9 were positively correlated (P<0.01) with atrial fibrosis (collagen volume fraction index), as were the <i>HIF-1α</i>, <i>TGF-β</i><i>₁</i> and <i>MMP-9</i> mRNA levels (P<0.01) and the mRNA levels between <i>MMP-9</i> and <i>TGF-β</i><i>₁</i> (P<0.01). During the process of atrial fibrosis in ISO-induced rats, HIF-1α promotes the expression of TGF-β₁ and MMP-9 protein, and thus is involved in in atrial fibrosis.