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

Abstract

The insulin-PI3K-mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin-sensitivity via insulin-PI3K-mTOR 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 siRNA (siLin28a) or lin28a cDNA (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 IGF1R, p-Akt, p-mTOR and p-p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre-treatment abolished the effects of increased p-mTOR 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-mTOR dependent pathway.

miR-613 suppresses ischemia-reperfusion-induced cardiomyocyte apoptosis by targeting the programmed cell death 10 gene

“…Thus far, numerous miRNAs have been reported to be associated with myocardial I/R injury by regulating target genes, including miR-451, miR-133a, and Lin28a (11)(12)(13). The current study investigated the potential role of miR-613 in myocardial I/R injury and results indicated that the level of miR-613 expression decreased by 43% in H9c2 cells after H/R treatment in comparison to the level of expression in the controls.…”

Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning

“…It seems that RIC induced cardioprotection is abolished during acute hyperglycemia because of the activation of mTOR-mediated insulin negative feedback loop in diabetic conditions [77,78]. In the diabetic model, the pre-treatment with rapamycin induces an improvement of the cardiac function [78,79].…”

ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK‐FoxO3a Signal Pathway

“…Cardiac function was determined by echocardiography (VisualSonics, Canada) and invasive hemodynamic evaluation by a 1.4 French micromanometer (Millar Instruments, USA) at different time points after ischemia/reperfusion. Echocardiography was performed under anesthesia using a 30 MHz transducer on a Vevo 2100 ultrasound system (VisualSonics, Canada) as previously described [ 20 ].…”