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CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 α Activation

Singh, SP    (Departments of Pharmacology and Medicine, New York Medical College, Valhalla, New York, USA   ); McClung, JA    (Departments of Medicine, New York Medical College, Valhalla, New York, USA   ); Bellner, L    (Departments of Pharmacology and Medicine, New York Medical College, Valhalla, New York, USA   ); Cao, J    (Departments of Pharmacology and Medicine, New York Medical College, Valhalla, New York, USA   ); Waldman, M    (Departments of Pharmacology and Medicine, New York Medical College, Valhalla, New York, USA   ); Schragenheim, J    (Departments of Pharmacology and Medicine, New York Medical College, Valhalla, New York, USA   ); Arad, M    (Leviev Heart Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Israel   ); Hochhauser, E    (Cardiac Research Laboratory, Felsenstein Medical Research Institute and Sackler School of Medicine, Tel-Aviv University, Israel   ); Falck, JR    (Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA   ); Weingarten, JA    (Weill Cornell Medicine, New York, USA   ); Peterson, SJ    (Weill Cornell Medicine, New York, USA   ); Abraham, NG    (Departments of Medicine, New York Medical College  );
  • 초록  

    We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1α, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1α. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome.


  • 주제어

    Inflammation .   Oxidant stress .   Cardiomyopathy .   Metabolic syndrome .   Hypertension .   Myocardial biology.  

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