Abstract
Volatile anesthetic-induced preconditioning (APC) has been shown to pharmacologically precondition the myocardium, providing protection from an ischemia-reperfusion injury. However, APC is attenuated or even eliminated in diabetic individuals and in the presence of acute hyperglycemia with the underlying mechanism(s) being unknown. In this study, we used ventricular cardiomyocytes (CMs) differentiated from non-diabetic and type II diabetic-induced pluripotent stem cells (N-iPSCs and DM-iPSCs, respectively) to investigate the influence of a high glucose environment and genetic background on APC. Differentiated CMs were identified using cardiac-specific immunostaining and expression of green fluorescent protein under the transcriptional control of cardiac promoter myosin light chain-2v, a genetic construct delivered by lentiviral vector. N-iPSC- and DM-iPSC-derived CMs were exposed to varying glucose environments (11 mM and 25 mM). Confocal microscopy was utilized to measure mitochondrial membrane potential and mitochondrial permeability transition pore opening (mPTP) in CMs. The volatile anesthetic isoflurane depolarized mitochondria in N-iPSC-derived CMs via opening of the mitochondrial adenosine triphosphate-sensitive potassium channel; however, isoflurane depolarized mitochondria to a significantly lower level in diabetic-derived cardiomyocytes and in the presence of 25 mM glucose. APC delayed mPTP opening in both N-iPSC- and DM-iPSC-derived CMs in 11 mM glucose environment only. We have established an in vitro model based on directed differentiation of ventricular CMs from N-iPSCs and DM-iPSCs that allows us the unique opportunity to conduct comparative studies to address the inability of diabetic individuals to be preconditioned with anesthetics. Our preliminary results indicate for the first time that both a high glucose environment and a diabetic background have detrimental effects on the efficiency of APC to protect CMs from an ischemia-reperfusion injury.
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