Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway
Authors: John R Falck
Peter L Tsenovoy
Ellen A Thompson
Robert Touchon
Nader G Abraham
Jian Cao
Rita Rezzani
Komal Sodhi
Joseph I Shapiro
Journal: Prostaglandins & other lipid mediators (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Angiogenesis; Epoxyeicosatrienoic acid; Heme oxygenase-1; Myocardial infarction; Wnt1.
Affiliations: Chinese PLA General Hospital, Beijing 100853, China., New York Medical College, Valhalla, NY, United States., Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States., University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States., New York Medical College, Valhalla, NY, United States; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States. Electronic address: .

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&lt;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&lt;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&lt;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. 

Retracted: No

PubPeer comments:
 The acting blot in figure 7B is quite similar to the actin blot that has appeared in five other publications from this group. The resolution is lower, but the features are eerily similar. It is shown as it appeared in the original figure and also enlarged and aligned with two examples of this recurring blot. Five examples are shown in: https: pubpeer.com publications 013834175109D0766BBE70E88E2353 ![file] Figure 7C has a series of lanes that are remarkably similar to a blot formed by duplication of four lanes that has made appearances in three other papers. In each appearance it takes on a new identity. Commented on in: https: pubpeer.com publications 6BF6BCD78CF68B8B1DC710A72C8656 ![file] Figure 7D has actin lanes that look quite like lanes found in three other papers. Usually it hales as  actin , but once took the nom de plume of  AMPK . Commented on in: https: pubpeer.com publications 6BF6BCD78CF68B8B1DC710A72C8656 ![file] ,