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1 Hypertension and Vascular Reserach Division, Henry Ford Hospital, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: mlapoin1{at}hfhs.org.
Cyclooxygenase-2 (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 a)
myocardial infarction (MI) in vivo induces COX-2 expression chronically; and b) 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 NS398, a selective COX-2 inhibitor, or vehicle in drinking water for 2 weeks. After the treatment period, mice were subjected to 2D M-mode echocardiography to determine cardiac function. Hearts were then analyzed for determination of infarct size,
interstitial collagen content, BNP mRNA, myocyte cross-sectional area, and immunohistochemical staining for TGF
and COX-2. COX-2 protein, detected by
immunohistochemistry, was increased in MI hearts vs sham. MI resulted in increased left ventricular systolic and diastolic dimension and decreased ejection fraction, fractional shortening, and cardiac output. NS398 treatment partly reversed these detrimental changes. Myocyte cross-sectional area, a measure of hypertrophy, decreased 30% in the NS398 vs. 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
NS398-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. NS398 treatment reduced TGF immunostaining by 40%. NS398 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 following MI.
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