Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway.

BACKGROUND:Nobiletin is a natural polymethoxylated flavone that confers antioxidative, anti-inflammatory and anti-apoptotic efficacies. However, the potential benefits of nobiletin preconditioning on myocardial ischemia and reperfusion injury (MIRI) remains largely unknown. METHODS:MIRI was induced by ligation of the left anterior descending coronary artery and reperfusion. Pre-treatment with nobiletin, with or without PI3K/AKT inhibitor LY294002, was performed at the onset of reperfusion. Histological analyses, apoptotic evaluation, plasma biomarkers of myocardial injury, echocardiographic evaluation of cardiac function and myocardial levels of endoplasmic reticulum stress (ERS)-related molecules were observed. RESULTS:Nobiletin pre-treatment significantly deceased the infract size and number of apoptotic cells in the myocardium of MIRI rats, as determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Moreover, the plasma levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) also markedly decreased. In addition, pre-treatment with nobiletin restored the impaired cardiac systolic function, as evidenced by echocardiographic evaluation results. Importantly, pre-treatment with nobiletin significantly downregulated the myocardial mRNA and protein levels of ERS-related signal molecules, including GRP78, CHOP and caspase-12, but upregulated the levels of p-PI3K and p-AKT. Interestingly, co-treatment with LY294002 significantly abolished the benefits of nobiletin pre-treatment on cardiac function, myocardial apoptosis, cardiomyocyte injuries, and changes in myocardial levels of ERS-related signaling molecules. CONCLUSION:Nobiletin pre-treatment may alleviate MIRI probably via the attenuation of PI3K/AKT-mediated ERS-related myocardial apoptosis.