Abstract 18909: Poly-ADP-Ribose Polymerase (PARP) Inhibition Enhances Ischemic/Diabetic Wound Healing by Promoting Angiogenesis Through FOSL1
Introduction: Amputations resulting from poor perfusion associated with ischemic/diabetic wounds is a major health problem globally. To improve upon limb-salvage therapeutics, a better understanding of impaired angiogenesis in these challenging wounds is required. PARP is hyper-activated in both ischemic and diabetic conditions but it’s role and impact in impaired cutaneous healing remains unclear.
Methods: Using a previously established protocol, mice were made diabetic and ischemic by streptozocin infection and femoral artery ligation, respectively. Excisional wounds were created on the ventral surface of the thighs, followed by treatment with either PJ34 (a PARP inhibitor) or a vehicle. Daily digital photographs were used to monitor healing expressed as % of original sizes. Wound tissues were collected for molecular analysis of endothelial cell markers. Flow cytometry was used to analyze peripheral blood mononuclear cells for endothelial progenitor cell (EPCs) markers. In vitro angiogenesis assays were performed with HUVECs cultured under hyperglycemic and hypoxic conditions, with and without PARP inhibition (either by PJ34 or PARP1 siRNA).
Results: Improved wound healing resulting from PARP inhibition was observed as early as day 7 (68.7 ± 11.3% vs. 56.4 ± 25.5% in control group, p < 0.05). Western blot analysis showed PARP inhibition increased VEGFR2 by two-fold and eNOS by three-fold compared to control (p < 0.05). PARP inhibition also promoted EPC mobilization into the peripheral blood (VEGFR2+/CD133+ cells increased from 0.074% to 0.62% and VEGFR2+/CD34+ cells increased from 0.10% to 1.27%). In vitro angiogenesis assays showed that PARP inhibition enhances migration, invasion, and tube formation. RT-qPCR of known angiogenesis factors (CXCR7, FOSL1, ITGA6 and others) revealed that PARP inhibition increases FOSL1 expression by five-fold.
Conclusions: PARP inhibition increases FOSL1 gene expression, promotes angiogenesis, and enhances ischemic-diabetic wound healing. Because FOSL1 controls endothelial cell assembly into capillary tubes, investigating the detailed interaction between PARP and FOSL1 will foster discovery of new therapeutic targets to improve ischemic/diabetic wound healing.
Author Disclosures: D.K. Patel: None. X. Zhou: None. A. Friedman: None. A. Sidawy: None. L. Mishra: None. S. Sen: None. B. Nguyen: None.
- © 2016 by American Heart Association, Inc.