HIF-1α-mediated mitochondrial autophagy in the post-treatment protective effect of thyroxine against myocardial ischemia-reperfusion injury

This study aimed to investigate the role of HIF-1α-regulated mitochondrial autophagy in the protective effect of Thyroxine against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were randomly divided into five groups ( n = 10 each): Sham, I/R, L-Thyroxine (T4) post-treatment (20 µg/kg i.p. immediately after reperfusion), 2ME2 + I/R (15 mg/kg 2ME2 i.p. 30 min before ischemia), and 2ME2 + Thyroxine groups. The I/R model was established by ligating the left anterior descending coronary artery for 40 min followed by 120 min of reperfusion. Compared with the I/R group, Thyroxine treatment significantly up-regulated HIF-1α (2.<0.01) and BNIP3 (1.8 < 0.01) protein expressions, reduced the LC3-II/LC3-I ratio (0.6-fold, P < 0.01), Beclin-1 (0.<0.01) and P62 (0.40.01) accumulation, while increasing LAMP2 expression (1.6-fold, P < 0.01). Thyroxine treatment reduced ROS production from 80% to 40% DHE-positive nuclei ( P < 0.01), increased ATP content from 45% to 75% of sham levels ( P < 0.05), restored mitochondrial membrane potential (JC-1 red/green ratio increased from 0.4 to 0.8, P < 0.01), and decreased myocardial infarct size from 45% to 20% of the area at risk ( P < 0.01). These protective effects were abolished by the HIF-1α inhibitor 2ME2 pre-treatment. Thyroxine reduced the area of myocardial infarction and promoted mitochondrial autophagy by activating the HIF-1α/BNIP3 signaling pathway.