title: Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway.
abstract: Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.
authors: Chinese PLA General Hospital, Beijing 100853, China.
authors: Jian
authors: J
authors: Cao
authors: New York Medical College, Valhalla, NY, United States.
authors: Peter L
authors: PL
authors: Tsenovoy
authors: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States.
authors: Ellen A
authors: EA
authors: Thompson
authors: University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors: John R
authors: JR
authors: Falck
authors: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States.
authors: Robert
authors: R
authors: Touchon
authors: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States.
authors: Komal
authors: K
authors: Sodhi
authors: New York Medical College, Valhalla, NY, United States.
authors: Rita
authors: R
authors: Rezzani
authors: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States.
authors: Joseph I
authors: JI
authors: Shapiro
authors: New York Medical College, Valhalla, NY, United States; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States. Electronic address: Nader_Abraham@NYMC.EDU.
authors: Nader G
authors: NG
authors: Abraham
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D015777:Eicosanoids / Q000819:agonists* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: C577139:2-(11-(nonyloxy)undec-8-enamido)succinic acid; D015777:Eicosanoids; D008565:Membrane Proteins; C495247:WNT1 protein, human; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D001224:Aspartic Acid; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Angiogenesis; Epoxyeicosatrienoic acid; Heme oxygenase-1; Myocardial infarction; Wnt1