Abstract 024: PGC-1α is a Critical Activator of HO-1 That Protects Against Cardiomyopathy in Diabetic Mice Through Recruitment of Mitochondrial Fusion Proteins and Function

Abstract

Introduction: Diabetes mellitus type 2 (DM2) is associated with cardiovascular complications, which are characterized by increased oxidative stress (ROS) and inhibition of anti-oxidant genes such as heme oxygenase (HO-1), Super oxide dismutase (SOD2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The latter that controls mitochondrial biogenesis, oxidative metabolism, and increased degradation of epoxyeicosatrienoic acids (EETs). Inhibition of these genes leads to increased myocardial stiffness and the development of cardiac hypertrophy and diastolic dysfunction. Aim: To assess whether PGC-1α plays a significant role in the development of diabetic cardiomyopathy in chronically obese mice. Methods: Leptin resistant (db/db) mice develop cardiomyopathy at the age of 5-6 month. Mice were treated with the EET agonist (EET-A) and with either lentivirus (Ln)- PGC-1α (Sh) or EET-A-Ln-PGC-1α scrambled for 3 additional months. Results: db mice exhibited impaired glucose tolerance, increased fasting blood glucose (366±21.9mg/dL vs.112±9.2 mg/dL, p<0.004), decreased oxygen consumption (VO 2 ) (25.09±1.1ml/min vs. 55.37±5.92ml/min, p<0.002) and heart weight (0.17±0.02g vs.0.12±0.006g, p<0.05) compared to WT mice. EET agonists treatments improved fasting glucose levels (366±21.9mg/dL vs. 134±18.4 mg/dL, p<0.007) and oxygen consumption (25.09±1.1ml/min vs. 33.7±3.75ml/min, p<0.018), and reduced heart weight (0.17±0.02g vs.0.13±0.002g, p<0.0026). HO-1 levels were increased in cardiac tissue 22-fold (p<0.016). The beneficial effects of EET were reversed inhibition of PGC-1α in the EET-A-Ln PGC-1α (Sh) not in EET-A-Ln-PGC-1α scrambled group. The inhibition of PGC-1α (52% reduction, p<0.022) resulted in a reduction in the beneficial effects of EET-A as manifested by weight gain, the development of severe dilated cardiomyopathy and the attenuation of HO-1 and SOD2 (90% and 76% reduction respectively, p<0.02) and a decrease in mitochondrial fusion proteins Mfn1, 2 and OPa1. Conclusion: EET mediated restoration of mitochondrial function by PGC1α is essential for the enhancement of HO-1-myocyte contraction and the prevention of LV dysfunction in chronic obesity.