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

BackgroundThe 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 ResultsTwo 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.ConclusionOur 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.

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord

“…6f). Peli1 is also reported to activate Akt [38,39], which is an important signaling in the regulation of neuropathic pain [40,41]. We found that knocking down Peli1 induced a significant reduction in Akt phosphorylation by 65.1% in the ipsilateral spinal cord, in comparison with scrambled shRNA control (Fig.…”

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…As a downstream of vascular endothelial growth factor receptor 2 (VEGFR2), Pellino1 induces the AKT and MAPK activated protein kinase 2 (MK2) phosphorylation to restore cell migration potential, proangiogenic responses and the wound healing ability with VEGFR2 deficiency in vitro and in vivo (114). Further studies demonstrated that Pellino1 is a novel proangiogenic molecule directly regulated by VEGFR (115). In mouse ischemia models, Pellino1 deletion increases oxidative stress, reduces cIAP2-NF-kB cell survival, decreases angiogenic response, and lowers tissue function (116).…”

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension

“…It appears that acute myocardial infarction-induced reduction of Pellino-1, an important angiogenic molecule under the control of vascular endothelial growth factor (VEGF) receptor 2/Flk-1, leads to reduced activities of AKT and eNOS ( Thirunavukkarasu et al, 2018 ). Therefore, we examined whether sunitinib may also affect AKT and eNOS activities via Pellino-1.…”

“…However, the intermediate molecules that link VEGF receptor and AKT is largely unknown. A recent study revealed that Pellino-1 is an important angiogenic molecule under the control of VEGFR2/Flk-1, as evident in that down regulated Pellino-1 expression during myocardial infarction contributes to suppression of VEGF-mediated angiogenesis via Pellino-1/AKT/eNOS pathway ( Thirunavukkarasu et al, 2018 ). In our experimental model, we found that application of sunitinib led to a significant decrease in the expression levels of Pellino-1 both in the rat artery tissue and in the primary cultured MAECs, suggesting that Pellino-1 may associate with sunitinib-induced decrease in ATK and eNOS activities.…”

“…In addition, VEGFR2/Flk-Pellino-1/AKT/eNOS signaling are also characterized as the potential regulators of angiogenesis and NO production in cardiomyocytes. In this study the authors demonstrated that the expression levels of Pellino-1 and the activities of AKT/eNOS in cardiomyocytes were attenuated by knocking down of VEGFR2, suggesting that Pellino-1 plays an important role in angiogenesis and cardiac repair downstream to VEGF/Flk ( Thirunavukkarasu et al, 2018 ). Given the facts that sunitinib has multiple pharmacological targets and that sunitinib treatment affects insulin clearance and insulin sensitivity, we therefore hypothesized that sunitinib-induced hypertension is associated with insulin resistance, insulin signaling and Pellino-1/AKT/eNOS pathways.…”