p38 MAPK-dependent eNOS upregulation is critical for 17β-estradiol-mediated cardioprotection following trauma-hemorrhage
p38 MAPK-dependent eNOS upregulation is critical for 17β-estradiol-mediated cardioprotection following trauma-hemorrhage
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DOI：
10.1152/ajpheart.91444.2007
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Chaudry, Irshad H.
中科院分区：
文献类型：
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作者：
Kan, Wen-Hong;Hsu, Jun-Te;Chaudry, Irshad H.
研究表明，p38 MAPK和由内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）在生理和病理生理条件下起着关键作用。虽然17 β-雌二醇（E-2）的管理，保护心血管损伤的创伤出血，E-2产生这些作用的机制仍然未知。我们的目的是确定E-2介导的心肌p38 MAPK激活和随后的eNOS表达/磷酸化是否会保护创伤出血后的心脏。为了研究这一点，雄性Sprague-Dawley大鼠经历软组织创伤（中线剖腹术）和失血性休克（平均血压35-40 mmHg，持续90分钟），然后进行液体复苏。在载体（环糊精）或E-2（100 μ g/kg）处理前30分钟，用特异性p38 MAPK抑制剂SB-203580（SB; 2 mg/kg）和非选择性NO合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME; 30 mg/kg）预处理动物，随后复苏，并在2小时后处死。测量心血管功能和其他参数。创伤出血后给予E-2可增加心脏p38 MAPK活性、eNOS表达和Ser（1177）磷酸化以及血浆和心脏组织中硝酸盐/亚硝酸盐水平;这些与正常化的心脏功能相关，SB可逆转这些情况。此外，E-2还防止创伤诱导的细胞因子（IL-6和TNF-α）、趋化因子（巨噬细胞炎性蛋白-2和龙氨酸诱导的中性粒细胞趋化因子-1）和ICAM-1的增加，这可通过L-NAME给药逆转。创伤性出血后给予E-2可减弱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，SB和L-NAME治疗可逆转这些指标。E-2对创伤出血后心脏功能和组织保护的有益作用部分通过激活p38 MAPK和随后的eNOS表达和磷酸化介导。
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 beta-estradiol (E-2) protects cardiovascular injury from trauma-hemorrhage, the mechanism by which E-2 produces those effects remains unknown. Our objective was to determine whether the E-2-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 E-2 (100 mu g/kg) treatment, followed by resuscitation, and were killed 2 h thereafter. Cardiovascular performance and other parameters were measured. E-2 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, E-2 also prevented traumahemorrhage-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 E-2 following traumahemorrhage 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-2 on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation.