Why there are two cyclooxygenase isozymes
Why there are two cyclooxygenase isozymes
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DOI：
10.1172/jci13271
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发表时间：
2001-06-01
影响因子：
15.9
通讯作者：
Langenbach, R
中科院分区：
文献类型：
--
作者：
Smith, WL;Langenbach, R
联系人：William L. Smith，513 Biochemistry Building，Department of Biochemistry and Molecular Biology，Michigan州立大学，东兰辛，Michigan 48824，USA。电话：（517）355-1604;传真：（517）353-9334;电子邮件：smithww@ msu。edu.此外，PGHS-2缺乏也阻碍胚泡着床和蜕膜化。PGI 2已被证明是参与该过程的前列腺素类，并且它也通过PGHS-2形成（表1）（12）。有趣的是，虽然前列腺素类似乎主要通过G蛋白连接受体发挥作用（5），但核过氧化物酶体增殖物激活受体PPARδ似乎介导了PGI 2在着床中的作用（12），这表明可能存在PGI 2影响基因表达的替代途径。新生儿发育。虽然人们普遍认为PGHS-1在发育中起作用，但很少有报告支持这一说法，最近的研究表明PGHS-2至少在新生儿发育中起着更重要的作用（13，14）。PGHS-2缺陷型小鼠出现严重的肾脏病理学，成年小鼠给予NSAID不会模拟这种病理学（2，3）。最初，一些研究者认为这种表型代表了PGHS-2敲除的补偿性伪影，但Komhoff等（2004）发现了这种表型。(13)最近表明，出生后用PGHS-2-选择性NSAID治疗引起新生小鼠肾脏肾小球直径严重减少。这与PGHS-2缺失小鼠中观察到的肾脏病理学相同（13），并且不能通过用PGHS-2选择性抑制剂处理成年小鼠引起。PGHS-2在小鼠中具有关键作用的另一个新生儿事件是动脉导管闭合（14）。尽管PGHS-1基因敲除小鼠的导管正常闭合，但约35%的PGHS-2基因敲除小鼠在出生后48小时内因导管未闭而死亡。在野生型小鼠中，通过免疫组织化学观察到PGHS-2而非PGHS-1在关闭期间在导管平滑肌细胞中显著诱导;然而，65%的考克斯-2缺失小鼠存活至断奶的事实表明PGHS-1可以发挥代偿作用。事实上，PGHS-1基因剂量从野生型到杂合性的减少进一步增加了动脉导管未闭的发生率，并将PGHS-2缺失小鼠的48小时存活率降低至约20%。因为PGHS-1的作用仅在PGHS-2不存在时才明显，所以PGHS-1不太可能参与野生型小鼠的导管闭合。这些例子表明PGHS-2在产后发育过程中具有关键作用。由于分娩过程涉及许多可能诱导PGHS-2的生理变化和应激，并且由于PGHS-2缺失小鼠在所有年龄段的存活率降低，因此寻找PGHS-2诱导促进正常新生儿发育的其他新生儿组织可能是有用的。
Address correspondence to: William L. Smith, 513 Biochemistry Building, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA. Phone:(517) 355-1604; Fax:(517) 353-9334; E-mail: smithww@ msu. edu. lation, PGHS-2 deficiency also impedes blastocyst implantation and decidualization. PGI2 has been demonstrated to be the prostanoid involved in this process, and it is also formed through PGHS-2 (Table 1)(12). Interestingly, although prostanoids appear to act primarily via G protein–linked receptors (5), the nuclear peroxisomal proliferator–activated receptor PPARδ appears to mediate the action of PGI2 in implantation (12), suggesting that alternative routes may exist by which PGI2 can influence gene expression. Neonatal development. Although it is widely believed that PGHS-1 acts in development, there are few reports available to support this claim, and recent studies suggest that PGHS-2 plays a more important role, at least in neonatal development (13, 14). PGHS-2–deficient mice develop a severe renal pathology that is not mimicked by administration of NSAIDs to adult mice (2, 3). Initially, some investigators believed that this phenotype represented a compensatory artifact of the PGHS-2 knockout, but Komhoff et al.(13) showed recently that postnatal treatment with a PGHS-2–selective NSAID caused a severe reduction in glomerular diameter in the neonatal mouse kidney. This was the same renal pathology as seen in PGHS-2–null mice (13) and could not be caused by treating adult mice with the PGHS-2–selective inhibitor. Another neonatal event in the mouse in which PGHS-2 has a key role is in the closure of the ductus arteriosus (14). Although the ductus closes normally in PGHS-1–null mice, about 35% of PGHS-2–null mice die with a patent ductus within 48 hours of birth. In wild-type mice, PGHS-2, but not PGHS-1, is seen by immunohistochemistry to be significantly induced in the smooth muscle cells of the ductus during closure; however, the fact that 65% of COX-2–null mice survived to weaning suggests that PGHS-1 can play a compensatory role. Indeed, a reduction in PGHS-1 gene dosage from wild-type to hetrozygosity further increases the incidence of patent ductus arteriosus and decreases the 48-hour survival of PGHS-2–null mice to about 20%. Because a role for PGHS-1 is only evident when PGHS-2 is absent, it is unlikely that PGHS-1 is involved in ductus closure in wild-type mice. These examples indicate that PGHS-2 has key roles during postpartum development. Because the birthing process involves a number of physiological changes and stresses that could induce PGHS-2, and because PGHS-2–null mice have decreased survival at all ages, it may be useful to search for other neonatal tissues in which PGHS-2 induction promotes normal neonatal development.