Abstract 6254: Nfkb Blockade Attenuates Cardiac Oxidative Stress And Improves Mitochondrial Function In Type II Diabetes
Type II diabetes is the most important predisposing factor for the development of cardiovascular disease. Recent findings from our lab suggest that cytokines and the nuclear transcription factor (NF-kB) contribute to oxidative stress and cardiac function. In this study, we determined the effect of NF-kB blockade on cardiac pathology in a mouse model of type II diabetes. Five week old obese db/db mice (control) and heterozygous lean mice (n = 8) were treated with PDTC (100mg/kg, orally) for 20 weeks. At the end of the study, left ventricular (LV) function was measured using echocardiography. Subsequently, mice were sacrificed and the LV was used for biochemical and mitochondrial assays. LV tissue and mitochondrial ROS and superoxide (O2−) were measured using electron spin resonance spectroscopy. The structural integrity of the mitochondrial membrane was measured using swelling assay and TEM analysis. Fractional shortening was decreased (24.29 ± 0.48) in control db/db mice relative to that of db/db mice treated with PDTC (38.06 ± 1.3). Control db/db mice had enhanced tissue NFkB activity accompanied by increased production of ROS and O2−. These animals had increased expression of NF-kB, RAGE, and gp91 phox, contributing to increased oxidative stress. Obese db/db mice also showed increased mitochondrial damage and mitochondrial ROS production which was accompanied by decreased ATP production. In contrast, treatment with PDTC attenuated oxidative stress, protected against mitochondrial dysfunction and preserved cardiac function. This study demonstrates that PDTC, a NFkB blocker, can mitigate oxidative stress, and improve mitochondrial structural integrity directly, through down-regulation of increased oxygen free radicals by its superoxide scavenging activity, thereby increasing ATP synthesis and thus restoring cardiac function in type II diabetes.