{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T20:47:41Z","timestamp":1764276461184},"reference-count":46,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2008,6]]},"abstract":"<jats:p> 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 17\u03b2-estradiol (E<jats:sub>2<\/jats:sub>) protects cardiovascular injury from trauma-hemorrhage, the mechanism by which E<jats:sub>2<\/jats:sub> produces those effects remains unknown. Our objective was to determine whether the E<jats:sub>2<\/jats:sub>-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\u201340 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<jats:sup>G<\/jats:sup>-nitro-l-arginine methyl ester (l-NAME; 30 mg\/kg) 30 min before vehicle (cyclodextrin) or E<jats:sub>2<\/jats:sub> (100 \u03bcg\/kg) treatment, followed by resuscitation, and were killed 2 h thereafter. Cardiovascular performance and other parameters were measured. E<jats:sub>2<\/jats:sub> administration following trauma-hemorrhage increased cardiac p38 MAPK activity, eNOS expression and phosphorylation at Ser<jats:sup>1177<\/jats:sup>, and nitrate\/nitrite levels in plasma and heart tissues; these were associated with normalized cardiac performance, which was reversed by SB administration. In addition, E<jats:sub>2<\/jats:sub> also prevented trauma-hemorrhage-induced increase in cytokines (IL-6 and TNF-\u03b1), chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-1), and ICAM-1, which was reversed by l-NAME administration. Administration of E<jats:sub>2<\/jats:sub> 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 E<jats:sub>2<\/jats:sub> on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation. <\/jats:p>","DOI":"10.1152\/ajpheart.91444.2007","type":"journal-article","created":{"date-parts":[[2008,4,11]],"date-time":"2008-04-11T21:10:21Z","timestamp":1207948221000},"page":"H2627-H2636","source":"Crossref","is-referenced-by-count":39,"title":["p38 MAPK-dependent eNOS upregulation is critical for 17\u03b2-estradiol-mediated cardioprotection following 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