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Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H368-H380. doi: 10.1152/ajpheart.00093.2017. Epub 2017 Jun 2.

EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice.

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Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York.
Chinese PLA General Hospital, Beijing, China.
Department of Drug Science/Section of Biochemistry, University of Catania, Catania, Italy.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
Leviev Heart Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel; and.
Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia.
Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York;


We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1α, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome.NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at


cardiomyopathy; heme oxygenase-1; hypertension; metabolic syndrome; myocardial biology; nephroblastoma overexpressed; oxidative stress

[Available on 2018-08-01]
[Indexed for MEDLINE]
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