Abstract 024: MicroRNAs and Anesthetic Cardioprotection in Diabetes
Introduction: MicroRNAs are endogenous small RNA molecules that regulate a wide range of cellular functions primarily through reduction of target protein expression. Several microRNAs have been shown to play important roles in cardiac injury, and also contribute to the development of diabetic complications and cardiac preconditioning. We utilized a model of the patient-specific induced pluripotent stem cells (iPSCs) differentiated into the cardiac lineage in order to delineate the environmental and cellular mechanisms responsible for overturning anesthetic cardioprotection in diabetes. We hypothesized that miR-21 contributes to cardioprotection conferred by anesthetics in human cardiomyocytes and that diabetic conditions compromise this protection in part via suppression of miR-21.
Methods: We have developed and validated a clinically relevant model of cardioprotection using human cardiomyocytes differentiated from the iPSCs derived from non-diabetic individuals (N-CM) and patients with type 2 diabetes mellitus (T2-CM).
Results: Our results indicate that cardiomyocytes derived from type 2 diabetes-specific stem cells recapitulate the phenotypic findings from type 2 diabetic patients. For instance, T2-CM exhibited a suppression of protein kinase B (Akt) and activation of glycogen synthase kinase-3β, compared to N-CM; indicating that this pathway is compromised in cardiomyocytes derived from diabetic individuals. In addition, we examined whether isoflurane could delay oxidative stress-induced mitochondrial permeability transition pore (mPTP) opening in T2-CM and found that the effects of isoflurane were significantly attenuated as compared to N-CM. Finally, isoflurane increased miR-21 abundance in N-CM, but not in T2-CM.
Summary: Diabetes and hyperglycemia substantially increase perioperative cardiovascular risk, with few mitigating strategies. Our data indicate an important role of miR-21 in isoflurane-induced cardioprotection and its impairment by diabetic conditions that may suggest new therapeutic targets for reducing perioperative cardiovascular morbidity and mortality in high-risk patients.
- © 2013 by American Heart Association, Inc.