Induction of placental heme oxygenase-1 is protective against TNFα-induced cytotoxicity and promotes vessel relaxation
Induction of placental heme oxygenase-1 is protective against TNFα-induced cytotoxicity and promotes vessel relaxation
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DOI：
10.1007/bf03401783
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发表时间：
2000-05-01
影响因子：
5.7
通讯作者：
St John, J
中科院分区：
文献类型：
--
作者：
Ahmed, A;Rahman, M;St John, J
背景：妊娠的特征是一个炎症样过程，这可能会加剧先兆子痫。血红素加氧酶（HO）酶产生一氧化碳（CO），诱导血管舒张和胆绿素，作为一种内源性antioxidant.Materials和方法：我们研究了HO-1和HO-2的表达和定位在正常和先兆子痫胎盘逆转录聚合酶链反应（RT-PCR），RNA酶保护试验，免疫印迹和免疫组化。此外，HO激活肿瘤坏死因子-α（TNF-α）诱导的胎盘损伤和胎儿-胎盘循环的影响进行了study.Results：我们提供了第一个证据HO作为一种内源性胎盘因子参与细胞保护和胎盘血管松弛的作用。HO-1显着高于足月，与孕早期胎盘表明其在胎盘血管发育和调节的作用。HO-1主要定位于血管外结缔组织中，其形成围绕发育中的血管的血管周收缩鞘。HO-2定位于毛细血管和绒毛间质，滋养细胞染色较弱。通过乳酸脱氢酶渗漏评估，HO-1的诱导导致胎盘绒毛外植体中TNF α介导的细胞损伤显著减弱（p < 0.01）。HO-1蛋白显着减少胎盘从妊娠并发子痫前期，与妊娠匹配的正常妊娠相比。这表明HO-1活化的损伤可能损害代偿机制，使胎盘易于细胞损伤和随后的母体内皮细胞活化。等距收缩研究表明，氯化血红素减少血管张力的61%，在U46619-preconstricted胎盘动脉。血红素诱导的血管舒张和CO的产生被抑制HO抑制剂，锡原卟啉IX。结论：我们的研究结果建立HO-1作为一种内源性系统，提供保护免受细胞毒性损伤的胎盘，确定HO-CO途径，以调节胎儿胎盘循环，并提供了一种新的方法来研究疾病的先兆子痫。
Background: Pregnancy is characterized by an inflammatory-like process and this may be exacerbated in preeclampsia. The heme oxygenase (HO) enzymes generate carbon monoxide (CO) that induces blood vessel relaxation and biliverdin that acts as an endogenous antioxidant.Materials and Methods: We examined the expression and localization of HO-1 and HO-2 in normal and preeclamptic placenta using reverse transcription polymerase chain reaction (RT-PCR), RNase protection assay, immunoblotting and immunohistochemistry. In addition, the effect of HO activation on tumor necrosis factor-alpha (TNF alpha) induced placental damage and on feto-placental circulation was studied.Results: We provide the first evidence for the role of HO as an endogenous placental factor involved with cytoprotection and placental blood vessel relaxation. HO-1 was significantly higher at term, compared with first trimester placentae indicating its role in placental vascular development and regulation. HO-1 predominantly localized in the extravascular connective tissue that forms the perivascular contractile sheath around the developing blood vessels. HO-2 was localized in the capillaries, as well as the villous stroma, with weak staining of trophoblast. Induction of HO-1 caused a significant attenuation of TNF alpha-mediated cellular damage in placental villous explants, as assessed by lactate dehydrogenase leakage (p < 0.01). HO-1 protein was significantly reduced in placentae from pregnancies complicated with preeclampsia, compared with gestationally matched normal pregnancies. This suggests that the impairment of HO-1 activation may compromise the compensatory mechanism and predispose the placenta to cellular injury and subsequent maternal endothelial cell activation. Isometric contractility studies showed that hemin reduced vascular tension by 61% in U46619-preconstricted placental arteries. Hemin-induced vessel relaxation and CO production was inhibited by HO inhibitor, tin protoporphyrin IX.Conclusions: Our findings establish HO-1 as an endogenous system that offers protection against cytotoxic damage in the placenta, identifies the HO-CO pathway to regulate feto-placental circulation and provides a new approach to study the disease of preeclampsia.