Abstract 15890: Hornerin, a Multifunctional Protein Critical to Non-VEGF-Mediated Angiogenesis, Plays a Determining Role in Neovascularization of the Infarct Post-mi
Introduction: Pathological angiogenesis is a hallmark of cancer and other ischemic/inflammatory diseases including remodeling after myocardial infarction (MI) and diabetic retinopathy. Inhibitors of vascular endothelial growth factor (VEGF) signaling have been tested for efficacy against various cancers in clinical trials, but have proven only moderately succesful. To identify factors other than VEGF involved in angiogenesis, we biopaned a phage display library against HUVECs in combination with negative selection against VEGF-mediated signaling. A separate phage display screen was carried out in vivo against the infarct border zone in mice at Day 4 post-MI.
Methods: One of the few phage clones in common between the two screens bound to endothelium in the infarct zone at Day 4 post-MI in the mouse model. The molecular binding target of this clone was identified as hornerin (Hrnr) by means of a phage-based proteomics approach. Hornerin belongs to the S100 family, and like other proteins in this family, is relevant in wound-healing post-MI. To study its function post-MI, we performed knock-down studies using siRNA specific for Hrnr. Further, in an effort to identify the potential mechanism of hornerin-induced neovascularization, we performed in vitro proliferation and apoptosis studies using human microvasculature endothelial cells (HMVECs).
Results: siRNA-mediated knock-down of Hrnr in post-MI mice prevented neovessel formation and further in vitro studies showed that Hrnr protected endothelial cells against ROS-induced apoptosis through activation of NF-kB (Fig. 1).
Conclusions: Inhibitors of Hrnr hold promise as an alternative anti-angiogenic therapy for various diseases including cancer and diabetic retinopathy. The upregulation of hornerin might also serve as therapy to protect endothelial cells against oxidative stress in the healing infarct after MI.
Author Disclosures: S. Dasa: None. M. Gutknecht: None. M. Seaman: None. B.A. French: Research Grant; Significant; Astra Zeneca. K.A. Kelly: Research Grant; Significant; Astra Zeneca.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.