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

Yumei Ye, Juan D. Martinez, Regino J. Perez-Polo, Yu Lin, Barry F. Uretsky, Yochai Birnbaum

Research output: Contribution to journalArticle

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Abstract

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-κB 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-κB in WT mice. It also increased myocardial COX2 activity. In eNOS-/- mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-κB 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-κB 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-κB, dependent. Activation of COX2 is dependent on iNOS.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

Fingerprint

Cyclooxygenase 2
Up-Regulation
Nitric Oxide Synthase Type III
Atorvastatin Calcium
Coronary Occlusion
Electrophoretic Mobility Shift Assay
Biotin
Immunoblotting
Reperfusion
Coronary Vessels
Enzyme-Linked Immunosorbent Assay

Keywords

  • Endothelial nitric oxide synthase
  • Inducible nitric oxide synthase
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

The role of eNOS, iNOS, and NF-κB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. / Ye, Yumei; Martinez, Juan D.; Perez-Polo, Regino J.; Lin, Yu; Uretsky, Barry F.; Birnbaum, Yochai.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 1, 07.2008.

Research output: Contribution to journalArticle

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AB - 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-κB 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-κB in WT mice. It also increased myocardial COX2 activity. In eNOS-/- mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-κB 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-κB 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-κB, dependent. Activation of COX2 is dependent on iNOS.

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