Novel Oral-edaravone Attenuates Diastolic Dysfunction of Diabetic Cardiomyopathy via Activating the Nrf2 Signaling Pathway

Abstract Background Diastolic dysfunction is the most common change of diabetic cardiomyopathy (DCM), but there is no effective clinical treatment at present. Oxidative stress plays a crucial role in the pathophysiological process of diabetic diastolic dysfunction including hypertrophy, apoptosis and fibrosis. The novel Oral-edaravone (OED) alleviates oxidative stress by scavenging free radical and may be suitable for the treatment of chronic diseases such as DCM. Methods DCM was induced by high sugar and high fat diet with intraperitoneal injection of streptozotocin (STZ) in rats. OED (3mg/kg/day) was administration for 4 weeks. Cardiac structure and function were measured using transthoracic echocardiography. H9C2 cardiomyocytes with Nrf2 transfection or not were incubated in glucolipotoxicity and treated with OED for 48 hours to further explore the mechanism. Results In type 2 diabetic rats,oral administration of OED for 4 weeks decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD). OED significantly improved E/A ratio and myocardium hypertrophy accompanied by decreased cross-sectional area of cardiomyocytes, proportion of apoptotic cells, collagen volume fractions and depositions of collagen I/III. In H9C2 cells, OED reduced reactive oxygen species (ROS), cell surface area and TUNEL-positive cells induced by glucolipotoxicity. OED remarkably up-regulated the expression of the Nrf2 signaling pathway both in vivo and in vitro, further promoted Nrf2 nuclear translocation and up-regulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase (NQO1) and heme oxygenase (HO-1). Moreover, Nrf2 gene silencing abolished the protective effect of OED in H9c2 cells. Conclusion Our findings demonstrated that OED treatment has the therapeutic potential to ameliorate diastolic dysfunction of DCM. The effect is mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocytes hypertrophy, apoptosis and fibrosis via activating the Nrf2 signaling pathway.