Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy
Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy
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DOI：
10.1172/jci927
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发表时间：
1998-03-01
影响因子：
15.9
通讯作者：
Ahmed, A
中科院分区：
文献类型：
--
作者：
Acevedo, CH;Ahmed, A
一氧化氮被认为是妊娠期间子宫肌层收缩力的内源性抑制剂，一氧化碳 (GO) 与一氧化氮一样会增加 cGMP，并在血红素加氧酶 (HO) 将血红素降解为胆绿素 IX 的过程中产生。在此我们报告，与非妊娠子宫肌层相比，妊娠子宫肌层中 HO-1（诱导型）和 HO-2（组成型）的表达均高 15 倍以上 (n = 4，P < 0.001，P < 0.005，分别）。此外，HO诱导剂血红素（10μM）对HO-CO途径的激活完全抑制了自发收缩性（n = 3），在克雷布斯溶液中2 g张力下安装用于等长记录的子宫肌条中，催产素刺激的收缩（n = 5）也显着减少（P < 0.05）。逆转录PCR分析显示，在基础条件下，在非临产妊娠子宫肌层的外植体培养物中未检测到编码HO-1和HO-2的mRNA，然而，暴露于孕酮而非雌二醇-17β会诱导HO-1和HO-2 mRNA的表达。黄体酮还显着诱导 HO-1 蛋白质合成 (n = 4, P < 0.001)，而雌二醇-17 beta 没有影响 (n = 4)。在足月 (37-42 周妊娠) 非临产子宫肌层外植体中，孵育 2 小时后黄体酮 (10(-6) M) (n = 2) 和氯高铁血红素 (10 mu M) (n = 3) 刺激 CO 产生与 H2O 抑制剂锡原卟啉 IX (20 μM) 预孵育 1 小时可抑制氯高铁血红素的作用。这项研究清楚地证明了 H2O 在人类子宫肌层中的表达，并表明其诱导产生的 CO 限制了妊娠子宫肌层的子宫收缩力，表明 HO-CO-cGMP 途径在维持妊娠期间子宫静止状态中的作用。
Nitric oxide was proposed as an endogenous inhibitor of myometrial contractility during pregnancy, Carbon monoxide (GO) like nitric oxide increases cGMP and is generated during the degradation of heme to biliverdin IX by heme-oxygenases (HO), Here we report that the expression of both HO-1 (inducible) and HO-2 (constitutive) were > 15-fold higher in pregnant myometrium compared to nonpregnant myometrium (n = 4, P < 0.001, P < 0.005, respectively). Moreover, the activation of the HO-CO pathway by the HO inducer, hemin (10 mu M), completely inhibited spontaneous contractility (n = 3), Oxytocin-stimulated contractions (n = 5) were also significantly reduced (P < 0.05) in myometrial strips mounted for isometric recording under 2 g tension in Krebs solution. Reverse transcription-PCR analysis revealed that mRNA encoding HO-1 and HO-2 was undetected in explant cultures of nonlaboring pregnant myometrium under basal conditions, however, exposure to progesterone, but not estradiol-17 beta, induced the expression of HO-1 and HO-2 mRNAs. Progesterone also significantly induced HO-1 protein synthesis (n = 4, P < 0.001) while estradiol-17 beta had no effect (n = 4), In term (37-42-wk gestation) nonlaboring myometrial explants, CO production was stimulated by progesterone (10(-6) M) (n = 2) and hemin (10 mu M) (n = 3) after 2 h of incubation and the effect of hemin was inhibited by 1 h of preincubation with the HO inhibitor tin protoporphyrin IX (20 mu M) This study clearly demonstrates the expression of HO in the human myometrium and shows that its induction produces CO that limits uterine contractility in pregnant myometrium indicating a role for the HO-CO-cGMP pathway in the maintenance of the quiescent state of the uterus during pregnancy.