Interaction Between Inducible Cyclooxygenase and Nitric Oxide Synthase in Cardiac Remodeling

1 . COX-2^<-/->基因敲除小鼠心脏和肾脏纤维化发生机制众所周知，环氧化酶(COX)-2基因敲除小鼠随着年龄的增长，心脏和肾脏纤维化发生，提示心脏和肾脏中COX-2组成性表达参与了纤维化的调控。为了研究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^<-/->小鼠中前列腺素合成酶和基质金属蛋白酶（MMPs）的表达。8周龄COX-2^<-/->小鼠出现轻度肾功能障碍（血尿素氮升高）和肾皮质变薄。COX-2^<-/->小鼠肾脏中膜结合PGE合成酶（mPGES）和MMP-2的表达较WT小鼠降低，且与肾脏PGE_2含量降低有关。16周龄COX-2^<-/->小鼠肾脏出现轻度间质纤维化，mPGES和MMP-2的表达甚至在心脏也下降。综上所述，PGE_2…More来源于功能偶联的COX-2和mPGES，对于解决肾脏纤维化至关重要，也可能是心脏纤维化。COX-2与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衍生产物参与了梗死后心室重构的发展。此外，已知COX-2蛋白与梗死周围和部位的iNOS协同诱导。因此，我们利用WT和iNOS敲除小鼠（iNOS^<-/->）研究了COX-2在梗死后心肌中的作用以及COX-2与iNOS之间的相互作用。小鼠随机分为给药组和ns -398组。72h后，TTC染色检测梗死面积，免疫组化染色检测COX-2和iNOS蛋白表达。COX-2的表达在两株和相似株中均有升高。在WT梗死周围cox -2阳性细胞附近观察到iNOS。与iNOS^<-/->小鼠相比，WT和iNOS^<-/->小鼠的梗死面积和死亡率没有差异。NS-395在WT小鼠中有减小梗死面积的趋势，但在iNOS^<-/->小鼠中却增加了梗死面积和死亡率。我们推测1)COX-2蛋白的增加对梗死后心肌具有有害作用，2)共表达的iNOS调节COX-2的有害作用。因此，COX-2可能发挥心脏保护或有害作用，这取决于iNOS的活性。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