Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition.

Lin28a has been found to enhance glucose uptake and insulin sensitivity. Lin28a alleviates cardiac dysfunction under various pathological conditions. However, the effects and underlying mechanisms of Lin28a on diabetic cardiomyopathy (DCM) are not well-understood. The aim of this study was to determine whether Lin28a protects against DCM and the potential mechanisms. Two to three days old mouse neonatal primary cardiomyocytes were randomized for treatment with adenoviruses harboring Lin28a and mammalian sterile 20-like kinase 1 (Mst1) short hairpin RNA, 48 hr before culturing in normal or high glucose medium. Cardiomyocyte apoptosis, autophagy, mitochondrial morphology, adenosine triphosphate content, and cytokine levels in the high glucose or normal conditions were observed between all groups. Either Lin28a overexpression or Mst1 knockdown alleviated mitochondrial ultrastructure impairment, decreased cytokine levels, inhibited apoptosis, and enhanced autophagy in primary neonatal mouse cardiomyocytes treated with high glucose. Importantly, the protective effects of Lin28a and Mst1 disappeared after treatment with 3-methyladenine, an autophagy inhibitor. Interestingly, in Mst1 knockdown cardiomyocytes, Lin28a overexpression failed to further enhance autophagy and alleviate high glucose-induced cardiomyocyte injury, which implies the protective roles of Lin28a counteracting high glucose-induced cardiomyocyte injury are dependent on Mst1 inhibition. Furthermore, co-immunoprecipitation and immunofluorescence double staining suggested that there were no direct interactions between Mst1 and Lin28a. Lin28a increased the expression of Akt, which inhibited the activation of Mst1-mediated apoptotic pathways.