Aldose reductase (AR), glycogen synthase kinase 3 beta (GSK3β), and autophagy in ischemic hearts

Abstract

Our objective in this study was to investigate if AR pathway mediated I/R injury is linked to changes in phosphorylation of GSK3β and autophagy. Utilizing an isolated Langendorff perfusion system, hearts from adult wildtype (WT) mice, AR transgenic (ARTg) and AR knockout (ARKO) mice were isolated and treated with/without GSK3β inhibitors and were perfused under normoxic conditions for 30 minutes, followed by 30 minutes of ischemia and 60 minutes of reperfusion. Lactate dehydrogenase(LDH) and creatine kinase(CK) release were measured in the perfusate after reperfusion. Left ventricular developed pressure (LVDP) was measured to determine myocardial function. ARTg mice hearts displayed increased LDH and CK release. LVDP was significantly decreased after reperfusion in ARTg hearts. P-GSK3β was also significantly decreased in ARTg mice hearts compared to WT and ARKO hearts. Treatment with GSK3β inhibitors improved cardiac recovery and decreased LDH and CK release. AR deletion and treatment with SB216763 and LiCl showed significantly higher levels of p-GSK3β/total GSK3β. Our studies highlight AKT in mediating I/R injury. Autophagy related gene, beclin-1, was significantly decreased in ARTg mice. In conclusion, AR pathway mediates I/R injury via decreased AKT activation, decreased phosphorylation of GSK3β, and impaired autophagy. Research supported by NIH training grant.