Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition

Abstract

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. K E Y W O R D S apoptosis, autophagy, diabetic cardiomyopathy, Lin28a, Mst1 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: You P, Cheng Z, He X, et al. Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition. J Cell Physiol. 2020;235:4455-4465.

Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy

“…The same research group later showed that melatonin, a hormone that helps maintain circadian rhythm, reduces apoptosis and alleviates mitochondrial dysfunction by inhibiting MST1 phosphorylation and promoting SIRT3 expression in DCM 129 . Another group found that LIN28A, a LIN-28 family RNA-binding protein that acts as a posttranscriptional regulator of genes involved in developmental timing and self-renewal in embryonic stem cells, protects against diabetic cardiomyopathy through MST1 inhibition 130 . Their study further clarified that LIN28a increases the expression of AKT and inhibits the activation of MST1-mediated apoptotic pathways.…”

Advances in the study of RNA-binding proteins in diabetic complications

“…As all these above-mentioned mechanisms are downstream effectors, more researchers are looking for the common 'keys' to these mechanisms, namely their upstream regulators, that acts as a master regulatory factor to the development and progression of DM and its complications. Recent studies have then found that RNA binding proteins (RBPs) such as human antigen R (HuR) and TTP (Tristetraprolin) are directly involved in vasculopathy in diabetes or diabetic complications by regulating the expression and stability of vascular endothelial growth factor (VEGF) mRNA [ [16] , [17] , [18] ], while LIN28 mediates the handling and ripening of let7 microRNA (miRNA), which promotes the uptake of blood glucose by tissue cells to inhibit the progression of DM and its complications [ [19] , [20] , [21] ].…”

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

“…Interestingly, the Lin28a-dependent protective effect against high glucose conditions was abolished when autophagy was inhibited by 3-metil-adenine. This data suggest that autophagy is involved in in vitro cardio protection ( 113 ). miR34a is upregulated in the myocardial tissue of diabetic patients and mice, leading to DCM ( 114 ).…”

“…Several cardioprotective molecules regulating the autophagic flux in DCM have been described. Lin-28 homolog A (Lin28a) is decreased in high glucose conditions and inhibits the mammalian sterile 20-like kinase 1 (Mst1) ( 113 ). Lin28a overexpression activates autophagy in cardiomyocytes ( 113 ).…”

“…Lin-28 homolog A (Lin28a) is decreased in high glucose conditions and inhibits the mammalian sterile 20-like kinase 1 (Mst1) ( 113 ). Lin28a overexpression activates autophagy in cardiomyocytes ( 113 ). Interestingly, the Lin28a-dependent protective effect against high glucose conditions was abolished when autophagy was inhibited by 3-metil-adenine.…”