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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2627    most recent 91444.2007v2 91444.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kan, W.-H. Articles by Chaudry, I. H. PubMed PubMed Citation Articles by Kan, W.-H. Articles by Chaudry, I. H.

p38 MAPK-dependent eNOS upregulation is critical for 17β-estradiol-mediated cardioprotection following trauma-hemorrhage

Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 11 December 2007 ; accepted in final form 3 April 2008

Studies have shown that p38 MAPK and nitric oxide (NO), generated by endothelial NO synthase (eNOS), play key roles under physiological and pathophysiological conditions. Although administration of 17β-estradiol (E₂) protects cardiovascular injury from trauma-hemorrhage, the mechanism by which E₂ produces those effects remains unknown. Our objective was to determine whether the E₂-mediated activation of myocardial p38 MAPK and subsequent eNOS expression/phosphorylation would protect the heart following trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent soft-tissue trauma (midline laparatomy) and hemorrhagic shock (mean blood pressure 35–40 mmHg for 90 min), followed by fluid resuscitation. Animals were pretreated with specific p38 MAPK inhibitor SB-203580 (SB; 2 mg/kg), and nonselective NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg) 30 min before vehicle (cyclodextrin) or E₂ (100 µg/kg) treatment, followed by resuscitation, and were killed 2 h thereafter. Cardiovascular performance and other parameters were measured. E₂ administration following trauma-hemorrhage increased cardiac p38 MAPK activity, eNOS expression and phosphorylation at Ser¹¹⁷⁷, and nitrate/nitrite levels in plasma and heart tissues; these were associated with normalized cardiac performance, which was reversed by SB administration. In addition, E₂ also prevented trauma-hemorrhage-induced increase in cytokines (IL-6 and TNF-), chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-1), and ICAM-1, which was reversed by L-NAME administration. Administration of E₂ following trauma-hemorrhage attenuated cardiac tissue injury markers, myeloperoxidase activity, and nitrotyrosine level, which were reversed by treatment with SB and L-NAME. The salutary effects of E₂ on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation.

nitric oxide synthase; cytokine; chemokine; myeloperoxidase