Abstract 15820: S-Nitrosoglutathione Reductase (GSNOR) Modulates Reendothelialization and Vascular Repair
Background: S-nitrosoglutathione (GSNO) reductase (GSNOR) is a widely expressed enzyme that degrades GSNO, a major source of nitric oxide (NO) bioactivity. GSNOR inhibition raises GSNO levels, increases protein S-nitrosylation and potentiates NO action. The role of GSNOR in vascular injury and repair is unknown.
Methods and Results: We evaluated vascular injury in wild type (WT) and GSNOR-deficient (GSNOR-/-) mice by examining neointimal formation, reendothelialization, and endothelial progenitor cell (EPC) mobilization after femoral and carotid artery wire injury. Neointimal formation was reduced by 41% in GSNOR-/- compared to WT mice (P=0.001). Aortic smooth muscle cells (SMCs) isolated from GSNOR-/- mice had reduced proliferation following PDGF-stimulation (P<0.005). In addition, GSNOR-deficiency reduced macrophage MCP-1 production by 45% (P<0.001) and plasma MCP-1 by 50% (P<0.001). Following wire injury, reendothelialization was enhanced in GSNOR-/- mice (day 3, 90% increase, P<0.02; day 7, 33% increase, P<0.02, vs. WT), and there were 60-110% more circulating sca-1+/KDR+ EPCs at baseline and 7days following wire injury (P<0.001, vs. WT). Circulating mononuclear cells and differentiated bone marrow-derived EPCs from GSNOR-/- mice expressed increased KDR by qPCR (20-fold increase, P<0.05, and 1.7-fold increase, P<0.036 respectively vs. WT), and circulating EPCs had increased KDR protein expression by flow cytometry (42% higher MFI vs. WT, P<0.001). Higher KDR expression and EPC levels in GSNOR-/- mice were associated with increased matrigel plug angiogenesis and 60% increased blood flow in hind limb ischemia experiments (day 7, P<0.001 vs. WT).
Conclusion: GSNOR deficiency results in reduced neointima formation likely due to attenuated SMC proliferation, improved reendothelialization, and increased KDR+ EPC mobilization. These data highlight a novel role for GSNOR in regulating the biological response to vascular injury, and identify GSNOR as a novel target to prevent intimal hyperplasia and promote reendothelialization following percutaneous coronary intervention.
- © 2011 by American Heart Association, Inc.