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The role of eNOS, iNOS, and NF-B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin

¹Department of Internal Medicine, ²Division of Cardiology, and ³Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Submitted 18 November 2007 ; accepted in final form 6 May 2008

Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS^–/– and iNOS^–/– mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-B dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS^–/– and iNOS^–/– mice received ATV (10 mg·kg^–1·day^–1; ATV⁺) or water alone (ATV^–) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-B in WT mice. It also increased myocardial COX2 activity. In eNOS^–/– mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-B was not activated by ATV in the eNOS^–/– mice. In the iNOS^–/– mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-B was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-B, dependent. Activation of COX2 is dependent on iNOS.

endothelial nitric oxide synthase; inducible nitric oxide synthase; nuclear factor-B

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