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The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin.
Am J Physiol Heart Circ Physiol 2008; 295(1):H343-51AJ

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

Authors+Show Affiliations

Department of Internal Medicine, Univ. of Texas Medical Branch, Galveston, TX 77555-0553, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18469150

Citation

Ye, Yumei, et al. "The Role of eNOS, iNOS, and NF-kappaB in Upregulation and Activation of Cyclooxygenase-2 and Infarct Size Reduction By Atorvastatin." American Journal of Physiology. Heart and Circulatory Physiology, vol. 295, no. 1, 2008, pp. H343-51.
Ye Y, Martinez JD, Perez-Polo RJ, et al. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol. 2008;295(1):H343-51.
Ye, Y., Martinez, J. D., Perez-Polo, R. J., Lin, Y., Uretsky, B. F., & Birnbaum, Y. (2008). The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. American Journal of Physiology. Heart and Circulatory Physiology, 295(1), pp. H343-51. doi:10.1152/ajpheart.01350.2007.
Ye Y, et al. The Role of eNOS, iNOS, and NF-kappaB in Upregulation and Activation of Cyclooxygenase-2 and Infarct Size Reduction By Atorvastatin. Am J Physiol Heart Circ Physiol. 2008;295(1):H343-51. PubMed PMID: 18469150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. AU - Ye,Yumei, AU - Martinez,Juan D, AU - Perez-Polo,Regino J, AU - Lin,Yu, AU - Uretsky,Barry F, AU - Birnbaum,Yochai, Y1 - 2008/05/09/ PY - 2008/5/13/pubmed PY - 2008/8/22/medline PY - 2008/5/13/entrez SP - H343 EP - 51 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 295 IS - 1 N2 - 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-kappaB 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-kappaB in WT mice. It also increased myocardial COX2 activity. In eNOS(-/-) mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-kappaB 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-kappaB 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-kappaB, dependent. Activation of COX2 is dependent on iNOS. SN - 0363-6135 UR - https://www.unboundmedicine.com/medline/citation/18469150/The_role_of_eNOS_iNOS_and_NF_kappaB_in_upregulation_and_activation_of_cyclooxygenase_2_and_infarct_size_reduction_by_atorvastatin_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.01350.2007?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -