Abstract
Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. 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. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl− channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). 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.
Highlights
Fusion between autophagosomes and endosomes–lysosomes, a process commonly referred to as the maturation or degradation[13]
To examine if volume-sensitive chloride channel is involved in hyperglycemia-induced cardiomyocyte injury, we evaluated the effect of high glucose on volume-sensitive outwardly rectifying anion channel (VSOR) Cl− currents
We demonstrated that high glucose-induced cardiomyocyte apoptosis is accompanied by the outflow of intracellular chloride ions, and the chloride channel blockers disodium salt hydrate (DIDS) and DCPIB protect cardiomyocytes from apoptosis by maintaining the homeostasis of intracellular chloride ions
Summary
Fusion between autophagosomes and endosomes–lysosomes, a process commonly referred to as the maturation or degradation[13]. The volume-sensitive outwardly rectifying anion channel (VSOR) is known to be involved in a variety of physiological processes including cell volume regulation, cell proliferation as well as cell turnover involving apoptosis[1]. The precise mechanisms underlying VSOR chloride channel-induced AVD in the context of hyperglycemia is still unknown. We probed the involvement of VSOR Cl− channel in hyperglycemia-induced apoptosis of CMs, and found that VSOR chloride currents promote apoptosis through inhibition of autophagy. These findings have implications for development of a new potential therapeutic strategy for DCM focusing on VSOR chloride channel
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