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作 者:徐和靖[1] 汪洋[1] 沈法荣[2] 金红峰[2] 朱立[3] 沈岳良[3] 陈莹莹[3]
机构地区:[1]温州医学院生理教研室,浙江温州325027 [2]浙江医院心内科,杭州310013 [3]浙江大学医学院生理教研室,杭州310006
出 处:《动物学报》2006年第4期690-697,共8页ACTA ZOOLOGICA SINICA
基 金:国家自然科学基金(No.30470635);温州市科技局项目(No.Y2003A099;No.WKW03070)资助~~
摘 要:通过诱导血红素氧化酶1(Hemeoxygenase1,HO1)可增强大鼠对抗心肌缺血复灌损伤。本文探讨线粒体ATP敏感性钾通道(MitochondrialATPsensitivepotassiumchannel,mitoKATP)、酪氨酸激酶(Proteintyrosinekinases,PTK)和核因子κB(NuclearfactorkappaB,NFκB)是否参与其中。SD大鼠腹腔注射HO1的诱导剂高铁血红素(hemin)50mg/kg,24h后取离体心脏给予30min缺血和120min复灌。结果发现,hemin可改善缺血-复灌(Ischemiareperfusion,IS)心脏的收缩功能,缩小心肌梗死面积;而HO1的抑制剂ZnPP可抑制hemin引起的HO1活性增加,并抵消hemin诱导的心肌保护作用。在腹腔注射hemin前给予mitoKATP通道阻断剂5HD(5mg/kg),与hemin+IS组相比,心脏的收缩功能明显下降,心肌梗死面积增大,LDH和CK释放增加。而在hemin预处理后24h,30min缺血前给予5HD灌流(100μmol/L)同样可阻断hemin诱导的心肌保护作用。hemin诱导的心肌保护作用亦可被PTK抑制剂genistein(10μmol/L)或NFκB抑制剂PDTC(100μmol/L)所取消。结果提示:hemin可诱导心肌HO1增加,保护心肌缺血-复灌性损伤,其作用可能与PTK和NFκB的激活有关,而mitoKATP通道在hemin诱导的心肌保护作用中可能扮演了启动因子和终末效应器双重角色。Activation of heme oxygenase 1 (HO-1) protects against ischemia-reperfusion injury in the heart. However, the downstream signaling mechanisms leading to its delayed anti-ischemic effects remain unclear. We hypothesized that HO-1 stimulation protects the heart via activation of mitochondrial ATP-sensitive potassium (mitoKATP) channel, nuclear transcription factor kappa B (NF-κB) and protein tyrosine kinases (PTK). Rats were treated with HO-1 inducer hemin. Twenty-four h later, hearts were perfused in Langendorff mode and subjected to 30 min of regional ischemia and 120 min of reperfusion. Hemin caused post-ischemic reduction in necrosis and improvement in myocardial performance, which was abolished by the HO-1 inhibitor, ZnPP. Pretreatment with 5 mg/kg of the mitOKATP channel antagonist 5-hydroxydecanoic acid (5-HD) before hemin administration abolished the effect of protection. Cardioprotection was also abrogated by 5-HD (100 μmol/L), which just given before 30 min of ischemia. Administration of either genistein (a PTK inhibitor, 10μmol/L) or PDTC (a NF-κB inhibitor, 100μmol/L) also could block hemin-induced cardioprection. The results indicated that hemin could protect against ischemia-reperfusion injury in the heart through enhancement of HO-1 activity, the mechanism might involve activation of PTK and NF-κB, and the mitoKATP channel might serve as both a trigger and an effector in hemin induced cardioprotection [ Acta Zoologica Sinica 52 (4): 690- 697, 2006].
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