Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

Abstract

Background The present study demonstrates that the ubiquitin E3 ligase, Pellino‐1 (Peli1), is an important angiogenic molecule under the control of vascular endothelial growth factor (VEGF) receptor 2/Flk‐1. We have previously reported increased survivability of ischemic skin flap tissue by adenovirus carrying Peli1 (Ad‐Peli1) gene therapy in Flk‐1+/− mice. Methods and Results Two separate experimental groups of mice were subjected to myocardial infarction (MI) followed by the immediate intramyocardial injection of adenovirus carrying LacZ (Ad‐LacZ) (1×109 pfu) or Ad‐Peli1 (1×109 pfu). Heart tissues were collected for analyses. Compared with wild‐type (WTMI) mice, analysis revealed decreased expressions of Peli1, phosphorylated (p‐)Flk‐1, p‐Akt, p‐eNOS, p‐MK2, p‐IκBα, and NF‐κB and decreased vessel densities in Flk‐1+/− mice subjected to MI (Flk‐1+/−MI). Mice (CD1) treated with Ad‐Peli1 after the induction of MI showed increased β‐catenin translocation to the nucleus, connexin 43 expression, and phosphorylation of Akt, eNOS, MK2, and IκBα, that was followed by increased vessel densities compared with the Ad‐LacZ–treated group. Echocardiography conducted 30 days after surgery showed decreased function in the Flk1+/−MI group compared with WTMI, which was restored by Ad‐Peli1 gene therapy. In addition, therapy with Ad‐Peli1 stimulated angiogenic and arteriogenic responses in both CD1 and Flk‐1+/− mice following MI. Ad‐Peli1 treatment attenuated cardiac fibrosis in Flk‐1+/−MI mice. Similar positive results were observed in CD1 mice subjected to MI after Ad‐Peli1 therapy. Conclusion Our results show for the first time that Peli1 plays a unique role in salvaging impaired collateral blood vessel formation, diminishes fibrosis, and improves myocardial function, thereby offering clinical potential for therapies in humans to mend a damaged heart following MI.

Keywords

• adenovirus
• animal models
• gene therapy
• genetics
• myocardial infarction
• myocardial revascularization