Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse
Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse
复制标题
DOI：
10.1152/ajpheart.00136.2003
复制
发表时间：
2004-04-01
影响因子：
4.8
通讯作者：
Yang, XP
中科院分区：
文献类型：
--
作者：
LaPointe, MC;Mendez, M;Yang, XP
环氧合酶(COX)-2在心肌缺血损伤动物模型中表达。最近的研究表明，COX-2产物参与了心脏炎症细胞的浸润和成纤维细胞的增殖。利用小鼠模型，我们质疑是否1)在体心肌梗死(MI)诱导慢性COX-2表达，以及2)抑制COX-2减少心肌梗死小鼠的胶原含量和改善心功能。结扎小鼠冠状动脉左前降支造成心肌梗死。2天后，给小鼠灌胃选择性COX-2抑制剂NS-398 3 mg/kg或饮水中的赋形剂2wk。治疗结束后，对小鼠进行二维M型超声心动图检查，以确定心功能。测定心肌梗死面积、间质胶原含量、脑利钠肽(BNP)mRNA、心肌细胞横截面积及转化生长因子-β和环氧合酶-2的免疫组织化学染色。免疫组织化学检测显示，心肌梗死组较假手术组COX-2蛋白表达增加。MI导致左心室收缩和舒张期内径增加，射血分数、短轴缩短率和心输出量降低。NS-398处理部分逆转了这些有害的变化。NS-398组心肌细胞横截面积较赋形剂组减少30%，但对BNP mRNA无影响。心肌间质胶原含量由假手术组的5.4+/-0.4%增加到心肌梗死组的10.4+/-0.9%，而NS-398组则降至7.9+/-0.6%。另一种COX-2抑制剂罗非昔布(MK-0966)也减少了心肌细胞横截面积和间质胶原含量。转化生长因子-β，胶原合成的关键调节因子，在心肌梗塞心脏中增加。NS-398处理使转化生长因子-β免疫染色减少40%。NS-398治疗对心肌梗死面积无影响。这些结果表明，COX-2产物参与了心肌梗死后心脏重构和功能缺陷的发生。因此，选择性抑制COX-2可能是减少心肌梗死后心肌细胞损伤的治疗靶点。
Cyclooxygenase (COX)-2 is expressed in the heart in animal models of ischemic injury. Recent studies have suggested that COX-2 products are involved in inflammatory cell infiltration and fibroblast proliferation in the heart. Using a mouse model, we questioned whether 1) myocardial infarction (MI) in vivo induces COX-2 expression chronically, and 2) COX-2 inhibition reduces collagen content and improves cardiac function in mice with MI. MI was produced by ligation of the left anterior descending coronary artery in mice. Two days later, mice were treated with 3 mg/kg NS-398, a selective COX-2 inhibitor, or vehicle in drinking water for 2 wk. After the treatment period, mice were subjected to two-dimensional M-mode echocardiography to determine cardiac function. Hearts were then analyzed for determination of infarct size, interstitial collagen content, brain natriuretic peptide (BNP) mRNA, myocyte cross-sectional area, and immunohistochemical staining for transforming growth factor (TGF)-beta and COX-2. COX-2 protein, detected by immunohistochemistry, was increased in MI versus sham hearts. MI resulted in increased left ventricular systolic and diastolic dimension and decreased ejection fraction, fractional shortening, and cardiac output. NS-398 treatment partly reversed these detrimental changes. Myocyte cross-sectional area, a measure of hypertrophy, was decreased by 30% in the NS-398 versus vehicle group, but there was no effect on BNP mRNA. The interstitial collagen fraction increased from 5.4 +/- 0.4% in sham hearts to 10.4 +/- 0.9% in MI hearts and was decreased to 7.9 +/- 0.6% in NS-398-treated hearts. A second COX-2 inhibitor, rofecoxib (MK-0966), also decreased myocyte cross-sectional area and interstitial collagen fraction. TGF-beta, a key regulator of collagen synthesis, was increased in MI hearts. NS-398 treatment reduced TGF-beta immunostaining by 40%. NS-398 treatment had no effect on infarct size. These results suggest that COX-2 products contribute to cardiac remodeling and functional deficits after MI. Thus selected inhibition of COX-2 may be a therapeutic target for reducing myocyte damage after MI.