Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse

• Published in: American journal of physiology. Heart and circulatory physiology 2004-04, Vol.286 (4), p.H1416-H1424
• Main Authors: LaPointe, Margot C, Mendez, Mariela, Leung, Alicia, Tao, Zhenyin, Yang, Xiao-Ping
• Format: Article
• Language: English
• Subjects: Animals; Cardiomegaly - drug therapy; Cardiomegaly - physiopathology; Collagen - metabolism; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Echocardiography; Fibrosis; Heart - drug effects; Heart - physiopathology; Immunohistochemistry; Isoenzymes - biosynthesis; Isoenzymes - metabolism; Lactones - therapeutic use; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - enzymology; Myocardial Infarction - physiopathology; Myocardium - enzymology; Myocardium - metabolism; Natriuretic Peptide, Brain - biosynthesis; Nitrobenzenes - therapeutic use; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides - therapeutic use; Sulfones; Transforming Growth Factor beta - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00136.2003

Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202 Submitted 13 February 2003 ; accepted in final form 5 December 2003 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)- 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- , a key regulator of collagen synthesis, was increased in MI hearts. NS-398 treatment reduced TGF- 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. echocardiography; NS-398; collagen; nonsteroidal anti-inflammatory drugs; prostanoids Address for reprint requests and other correspondence: M. C. LaPointe, Hypertension and Vascular Research Division, He