39,49-Dihydroxyflavonol Antioxidant Attenuates Diastolic Dysfunction and Cardiac Remodeling in Streptozotocin- Induced Diabetic m(Ren2)27 Rats

Background: Diabetic cardiomyopathy (DCM) is an increasingly recognized cause of chronic heart failure amongst diabetic patients. Both increased reactive oxygen species (ROS) generation and impaired ROS scavenging have been implicated in the pathogenesis of hyperglycemia-induced left ventricular dysfunction, cardiac fibrosis, apoptosis and hypertrophy. We hypothesized that 39,49-dihydroxyflavonol (DiOHF), a small highly lipid soluble synthetic flavonol, may prevent DCM by scavenging ROS, thus preventing ROS-induced cardiac damage. Methodology/Principal Findings: Six week old homozygous Ren-2 rats were randomized to receive either streptozotocin or citrate buffer, then further randomized to receive either DiOHF (1 mg/kg/day) by oral gavage or vehicle for six weeks. Cardiac function was assessed via echocardiography and left ventricular cardiac catheterization before the animals were sacrificed and hearts removed for histological and molecular analyses. Diabetic Ren-2 rats showed evidence of diastolic dysfunction with prolonged deceleration time, reduced E/A ratio, and increased slope of end-diastolic pressure volume relationship (EDPVR) in association with marked interstitial fibrosis and oxidative stress (all P,0.05 vs control Ren-2). Treatment with DiOHF prevented the development of diastolic dysfunction and was associated with reduced oxidative stress and interstitial fibrosis (all P,0.05 vs untreated diabetic Ren-2 rats). In contrast, few changes were seen in non