TY - JOUR
T1 - EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice
AU - Cao, Jian
AU - Singh, Shailendra P.
AU - McClung, John A.
AU - Joseph, Gregory
AU - Vanella, Luca
AU - Barbagallo, Ignazio
AU - Jiang, Houli
AU - Falck, J R
AU - Arad, Michael
AU - Shapiro, Joseph I.
AU - Abraham, Nader G.
N1 - Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grants HL-34300 to N. G. Abraham and HL-109015 to J. I. Shapiro, and by The Renfield Foundation, The Rockefeller University.
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/8/11
Y1 - 2017/8/11
N2 - 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-1β (PGC-1β) 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-1β, 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 http://ajpheart. physiology.org/content/early/2017/05/31/ajpheart.00093.2017.
AB - 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-1β (PGC-1β) 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-1β, 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 http://ajpheart. physiology.org/content/early/2017/05/31/ajpheart.00093.2017.
KW - Cardiomyopathy
KW - Heme oxygenase-1
KW - Hypertension
KW - Metabolic syndrome
KW - Myocardial biology
KW - Nephroblastoma overexpressed
KW - Oxidative stress
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U2 - 10.1152/ajpheart.00093.2017
DO - 10.1152/ajpheart.00093.2017
M3 - Article
C2 - 28576832
AN - SCOPUS:85027266278
SN - 0363-6135
VL - 313
SP - H368-H380
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -