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-IjBα, and NF-jβ 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 IjBα, 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.