Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin‐PI3K‐m TOR pathway

The insulin‐PI3K‐m TOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin‐sensitivity via insulin‐PI3K‐m TOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a si RNA (siLin28a) or lin28a c DNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size ( IS ), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS , improved LV ejection fraction ( LVEF ), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS , decreased LVEF , increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre‐treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF 1R, p‐Akt, p‐m TOR and p‐p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre‐treatment abolished the effects of increased p‐m TOR and p‐p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS , improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin‐PI3K‐m TOR dependent pathway.