Abstract 537: S-Nitrosoglutathione Reductase (GSNOR) Deficiency Reduces Vascular Inflammation and Atherosclerosis.
Introduction: Diminished NO production and altered NO bioavailability promote vascular inflammation and atherosclerosis. S-nitrosoglutathione reductase (GSNOR) controls cellular NO balance by degrading S-nitrosoglutathione (GSNO), which is a major source of nitric oxide (NO) bioactivity. GSNOR inhibition increases protein S-nitrosylation and potentiates NO action. The role of GSNOR in vascular inflammation is undefined, and the purpose of our investigation was to determine if GSNOR targeting dampens inflammation and reduces atherosclerosis.
Methods and results: We evaluated vascular inflammation and atherosclerosis in wild type (WT) and GSNOR-deficient (GSNOR-/-) mice. TNF-induced NFκB activation was reduced by 40% (p<0.05) in endothelial cells (ECs) isolated from GSNOR-/- compared to WT mice, which was accompanied by attenuated expression of P-selectin, E-selectin, and VCAM-1 (>34% reduction, p<0.05). Decreased EC adhesion molecule expression led to a 45% reduction in leukocyte rolling in the cremaster muscle microvasculature of GSNOR-/- mice (p<0.01). Deficiency of GSNOR also reduced macrophage production of MCP-1 and PDGF-stimulated aortic smooth muscle cell (SMC) proliferation (p<0.01). Furthermore, GSNOR-/- SMCs displayed a more mature phenotype compared to WT as evidenced by 105% increased mRNA expression of myosin heavy chain 11 (p<0.05), and 45% decreased expression of the SMC embryonic marker tropomyosin-4 (p<0.005). High fat-fed mice doubly deficient in ApoE and GSNOR (GSNOR-/-/ApoE-/-) had a 27% decrease in aortic atherosclerotic lesion area compared to ApoE deficient controls (p<0.03).
Conclusion: GSNOR deficiency attenuates vascular inflammation and atherosclerosis. These data highlight a novel role for GSNOR in regulating NO balance and vascular inflammation in vivo, thereby suggesting that GSNOR is an attractive therapeutic target for atherosclerotic vascular disease.
- © 2012 by American Heart Association, Inc.