Interaction Between Inducible Cyclooxygenase and Nitric Oxide Synthase in Cardiac Remodeling

一、COX-2基因敲除小鼠心脏和肾脏纤维化的发生机制众所周知，随着年龄的增长，环氧合酶(COX)-2基因敲除小鼠心脏和肾脏发生纤维化，提示COX-2在心脏和肾脏参与者中有结构性地表达对纤维化的调节。为了探讨COX-2在心脏和肾脏纤维化发展中的作用，我们比较了野生型(WT)和COX-2-/-&gt；小鼠前列腺素合成酶和基质金属蛋白酶(MMPs)的表达。8周龄的COX-2^&lt；-/-&gt；小鼠表现出轻度肾功能障碍(血尿素氮升高)和肾皮质变薄。与WT小鼠相比，COX-2小鼠肾脏膜结合型前列腺素E合成酶(MPGES)和基质金属蛋白酶-2的表达降低，并与肾脏前列腺素E_2含量降低有关。16周龄的COX-2^&lt；-/-&gt；小鼠肾脏表现为轻度间质纤维化，mPGES和基质金属蛋白酶-2的表达减少，甚至心脏也是如此。结论：前列腺素E_2…更多来自功能偶联的COX-2和mPGES对于解决肾脏和心脏中的纤维化是必不可少的。II.COX-2和诱导型一氧化氮合酶(INOS)在梗死后心肌中的相互作用最近的研究表明，COX-2衍生的产物参与了梗死后心室重构的发展。此外，已知COX-2蛋白与iNOS在梗死灶周围和部位协同诱导。因此，我们利用WT和iNOS基因敲除小鼠(iNOS^&lt；-/-&gt；)，研究了COX-2在心肌梗死后心肌中的作用以及COX-2和iNOS之间的相互作用。结扎冠状动脉左前降支造成在体心肌梗死小鼠，随机分为赋形剂组和NS-398治疗组。72h后，TTC染色检测心肌梗死面积，免疫组织化学染色检测COX-2、iNOS蛋白表达。COX-2在两种菌株中的表达均升高，且相似。WT梗死灶周边可见iNOS阳性细胞，靠近COX-2阳性细胞。WT和iNOS^&lt；-/-&gt；小鼠经赋形剂治疗后，脑梗塞面积和死亡率无差异。给予NS-395倾向于缩小WT小鼠的脑梗塞面积，但却加重了iNOS^&lt；-/-&gt；小鼠的脑梗塞面积和死亡率。我们推测：1)COX-2蛋白的增加对心肌梗死后的损伤有一定的作用；2)共表达的iNOS对COX-2的损伤作用有调节作用。因此，COX-2可能发挥心脏保护或损害作用，这取决于iNOS的活性。较少

I. Mechanism whereby cardiac and renal fibrosis develops in COX-2^<-/-> knockout mouseIt is well known that cardiac and renal fibrosis develops in cyclooxygenase(COX)-2 knockout mouse with aging, suggesting that COX-2 expressed constitutively in the heart and kidney participants the regulation of fibrosis. To investigate role of COX-2 on the development of cardiac and renal fibrosis, we compared the expression of prostanoid synthases and matrix metalloproteinases(MMPs) between wild-type (WT) and COX-2^<-/-> mice. Eight week-old COX-2^<-/-> mice showed mild renal dysfunction (elevation in blood urea nitrogen) and thinning of renal cortex. The expression of membrane-bound PGE synthase(mPGES) and MMP-2 was decreased in the kidney of COX-2^<-/-> mice, compared with WT mice, and associated with decrease in renal PGE_2 content. Sixteen week-old COX-2^<-/-> mice showed mild interstitial fibrosis in the kidney and decreased expression of mPGES and MMP-2 even in the heart. In conclusion, PGE_2 … More derived from functionally-coupled COX-2 and mPGES is essential for resolving fibrosis in the kidney, and probably in the heart.II. Interaction between COX-2 and inducible nitric oxide synthase(iNOS) in post-infarct myocardiumRecent studies have suggested that COX-2-derived products are involved in the development of post-infarct ventricular remodeling. In addition, it is known that COX-2 protein is induced in concert with iNOS around and at the site of the infarct. Thus, we investigated the role of COX-2 and the interaction between COX-2 and iNOS in post-infarct myocardium using WT and iNOS knockout mice(iNOS^<-/->). In vivo myocardial infarction was produced by ligation of the left anterior descending coronary artery Mice were randomly divided into vehicle- and NS-398-treated groups. Seventy-two h later, infarct size was detected by TTC staining and the expression of COX-2 and iNOS proteins was examined by immunohistolochemical staining. The expression of COX-2 was increased in both strains and similar. iNOS was observed in close proximity to COX-2-positive cells at the periphery of the infarct in WT. There is no difference in infarct size and the mortality between WT and iNOS^<-/-> mice treated with vehicle. Administration of NS-395 tended to reduce infarct size in WT mice but it rather exacerbated infarct size and the mortality in iNOS^<-/-> mice. We speculate that 1)increased COX-2 protein has the deleterious effect in post-infarct myocardium and 2)co-expressed iNOS modulates the deleterious effect of COX-2. Thus, COX-2 might exert the cardioprotective or detrimental action, dependent on iNOS activity. Less