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- MK 2, p-IκBα, and NF -κB and decreased vessel densities in Flk-1+/- mice subjected to MI (Flk-1+/- MI ). Mice ( CD 1) treated with Ad-Peli1 after the induction of MI showed increased ß-catenin translocation to the nucleus, connexin 43 expression, and phosphorylation of Akt, eNOS , MK 2, 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 CD 1 and Flk-1+/- mice following MI . Ad-Peli1 treatment attenuated cardiac fibrosis in Flk-1+/- MI mice. Similar positive results were observed in CD 1 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 .