SQSTM1/p62 is a polyubiquitin binding protein that is degraded by autophagy, displaying an inverse relationship in level with the autophagic activity 11, 12. The levels of LC3-II are proportional to the number of accumulated autophagosomes 10. Upon the initiation of autophagy, LC3 is processed from LC3-I (apparent molecular weight is 16 kDa) to LC3-II (14 kDa) 9. Hyperglycemia-induced autophagy may contribute to cardiotoxicity in hyperglycemia and diabetes although the precise role of autophagy in DCM has yet to be determined. Ample evidence has suggested an essential role for autophagy in the regulation of cardiac structure and function 9. This prompts the necessity for a better understanding of the mechanisms underlying the role of ROS accumulation in hyperglycemic cardiotoxicity and cardiac injury.Īutophagy is a highly conserved catabolic progress in which cells generate energy and metabolites by digesting and recycling their own organelles and macromolecucles 7, 8. Nonetheless, antioxidant therapy showed limited effects in the treatment of diabetic cardiac complication, particularly diabetic cardiomyopathy (DCM) and heart failure in humans 6. Hyperglycemia and diabetes mellitus are intimately linked to an increased prevalence of heart failure 3, 4, 5.
Hyperglycemia leads to an increase in oxidative stress by exacerbating glucose oxidation and mitochondrial generation of reactive oxygen species (ROS), resulting in DNA damage and accelerated apoptosis 1, 2. Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl − channel. In the present study, we found that chloride channel blockers, 4,4′-diisothiocya-natostilbene-2,2′- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl − channel and improved the viability of cardiomyocytes. Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients.
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