Atherosclerosis and its attendant complications such as myocardial infarction and stroke are the leading cause of mortality in the US and there is an urgent need for novel therapies to reduce the development and progression of atherosclerosis. Significant evidence supports the premise that inflammation promotes atherosclerosis and restenotic arterial remodeling after mechanical vascular injury. Therapies that target inflammation have potential to reduce atherosclerosis and improve the efficacy of arterial revascularization. Nitric oxide (NO) is a central regulator of vascular homeostasis and reduced NO bioavailability promotes vascular inflammation and atherogenesis. S-nitrosoglutathione reductase (GSNOR) governs NO signaling by enzymatically degrading S-nitrosoglutathione (GSNO) which is a major bioavailable NO depot. GSNOR inhibition increases GSNO which promotes S-nitrosylation of proteins. S-nitrosylation is a covalent modification that alters a broa range of signaling protein functions including enzymatic activity, subcellular localization, and protein stability. To gain insight into the molecular pathobiology of atherosclerosis, our investigations focused on understanding GSNOR control of endothelial inflammation. Preliminary studies demonstrate that GSNOR deficiency attenuates NF-kappa B-dependent endothelial activation and that GSNOR-deficient mice are protected from vascular inflammation, atherosclerosis, and restenosis. The central hypothesis of this proposal is that GSNOR-regulated S-nitrosylation critically controls endothelial NF-kB function and inflammatory signaling during vascular inflammation and repair. To precisely define GSNOR control of endothelial responses during vascular inflammation, two aims are proposed;
Specific Aim One will delineate the molecular basis of GSNOR-regulated endothelial NF-kB signaling, endothelial-leukocyte adhesion, and development of atherosclerosis, and Specific Aim Two will examine GSNOR regulation of endothelial repair following vascular injury. Medical Relevance The outlined investigations are clinically relevant because they will provide insight on the cellular mechanisms that govern atherosclerosis by defining how GSNOR and S-nitrosylation regulate endothelial inflammation. In vivo experiments will determine the therapeutic potential of targeting GSNOR to treat atherosclerosis and restenosis.
Significant evidence supports the premise that inflammation promotes atherosclerosis and arterial restenosis following therapeutic angioplasty. The central hypothesis of this proposal is that GSNOR and S-nitrosylation critically regulate endothelial inflammatory responses during vascular inflammation and repair. The experiments in this proposal will clarify the role of GSNOR in endothelial cell signaling and will determine the therapeutic potential of targeting GSNOR to treat atherosclerosis, restenosis, and vascular inflammation.
