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 HIF-1α, TGF-β1 and MMP-9 mRNA levels (P<0.01) and the mRNA levels between MMP-9 and TGF-β1 (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.
Highlights
Atrial fibrillation (AF), which is of one of the most common types of arrhythmia, shows high disabilityKey words: hypoxia inducible factor‐1α, atrial, fibrosis, transforming growth factor‐β1, matrix metalloproteinase‐9 and mortality rates in patients [1,2]
The majority of studies show that the renin‐angiotensin system (RAS) is activated by atrial fibrillation (AF), and simultaneously, as a major effecter molecule of the RAS in circulating and certain tissues [11], angiotensin II (AngII) levels increase and eventually induce atrial fibrosis [3]
The present study identified that AngII levels in the ISO and Rapa groups in myocardial tissue were significantly higher than the control group after seven days of subcutaneous multiple high‐dose continuous injection of ISO in rats, which implies that following ISO injection, RAS was activated and caused increased expression levels of AngII in myocardial tissue
Summary
Atrial fibrillation (AF), which is of one of the most common types of arrhythmia, shows high disability. The HIF‐1α inhibitor [9] [sirolimus, known as rapamycin (Rapa)] was administered to examine the protein expression and mRNA levels of AngII, HIF‐1α, transforming growth factor‐beta (TGF‐β1) and matrix metalloproteinase‐9 (MMP‐9) in myocardial tissue in the atrial fibrosis rat model, and the present study investigated their relevance and the possible mechanism of how HIF‐1α following the ISO injection would induce atrial fibrosis
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