Kan Wen-Hong, Hsu Jun-Te, Ba Zheng-Feng, Schwacha Martin G, Chen Jianguo, Choudhry Mashkoor A, Bland Kirby I, Chaudry Irshad H
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2627-36. doi: 10.1152/ajpheart.91444.2007. Epub 2008 Apr 11.
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 17beta-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 NG-nitro-l-arginine methyl ester (l-NAME; 30 mg/kg) 30 min before vehicle (cyclodextrin) or E2 (100 microg/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 Ser(1177), 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-alpha), 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.
研究表明，由内皮型一氧化氮合酶（eNOS）产生的p38丝裂原活化蛋白激酶（MAPK）和一氧化氮（NO）在生理和病理生理条件下起关键作用。尽管给予17β-雌二醇（E2）可保护心血管免受创伤性出血损伤，但其产生这些作用的机制仍不清楚。我们的目的是确定E2介导的心肌p38 MAPK激活以及随后的eNOS表达/磷酸化是否能在创伤性出血后保护心脏。为了研究这一点，雄性Sprague-Dawley大鼠接受软组织创伤（中线剖腹术）和失血性休克（平均血压35 - 40 mmHg，持续90分钟），随后进行液体复苏。在给予载体（环糊精）或E2（100μg/kg）治疗前30分钟，动物用特异性p38 MAPK抑制剂SB - 203580（SB；2mg/kg）和非选择性一氧化氮合酶抑制剂NG - 硝基 - L - 精氨酸甲酯（L - NAME；30mg/kg）进行预处理，随后进行复苏，并在2小时后处死。测量心血管功能和其他参数。创伤性出血后给予E2可增加心脏p38 MAPK活性、eNOS表达以及Ser(1177)位点的磷酸化，还可增加血浆和心脏组织中的硝酸盐/亚硝酸盐水平；这些与心脏功能正常化相关，而SB给药可逆转这种情况。此外，E2还可预防创伤性出血诱导的细胞因子（IL - 6和TNF - α）、趋化因子（巨噬细胞炎性蛋白 - 2和细胞因子诱导的中性粒细胞趋化因子 - 1）以及细胞间黏附分子 - 1（ICAM - 1）的增加，而L - NAME给药可逆转这种情况。创伤性出血后给予E2可减轻心脏组织损伤标志物、髓过氧化物酶活性和硝基酪氨酸水平，而SB和L - NAME治疗可逆转这种情况。E2对创伤性出血后心脏功能和组织保护的有益作用部分是通过激活p38 MAPK以及随后的eNOS表达和磷酸化介导的。
