Abstract
BackgroundDiabetes mellitus (DM) is a key contributing factor to the poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia-reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previously study, but the underlying mechanism remained unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury.Methods High-fat diet-fed streptozotocin-induced type 2 diabetic rats as recipients were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To unravel the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or Pink1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury.ResultsMitophagy was impaired in the diabetic lung subjected to IR injury, accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, both inhibitors of mitophagy and knockdown of Pink1 suppressed mitophagy, and reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected Pink1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed Pink1 expression and compromised the protective effect of adiponectin.ConclusionThese data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1-Pink1 signaling-mediated mitophagy in diabetic lung IR injury.
Adiponectin Ameliorates Lung Ischemia-Reperfusion Injury Through SIRT1-Pink1 Signaling-Mediated Mitophagy in Type 2 Diabetic Rats