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

Abstract

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.

Morphological and molecular changes of the myocardium after left ventricular mechanical support

“…6A-C) [96]. Furthermore, numerous animal studies have shown that hypertrophy and functional deterioration occur upon COX-2 overexpression, and are ameliorated by administration of COX-2 inhibitors, suggesting that COX-2 exerts cardiodepressive effects [98][99][100]. In summary, we demonstrated a negative regulation of COX-2 after ventricular unloading and suggest a central role for COX-2 in cardiomyocyte hypertrophy, since only COX-2 positive cardiomyocytes showed significant hypertrophy regression after LVAD (Fig.…”

PGE2stimulates human brain natriuretic peptide expression via EP4and p42/44 MAPK

“…We analyzed BNP and ␤-actin mRNA by real-time RT-PCR, which produced cDNAs of 241 bp (BNP) and 342 bp (␤-actin). PCR conditions and the sequences of primers and probes were reported previously (19). In brief, total RNA of NVM was extracted in Tri-Reagent (MRC) according to the manufacturer's instructions.…”

“…We previously showed that exogenous PGE 2 increased protein synthesis in myocytes, a marker of hypertrophic growth (26). Moreover, in a mouse model of myocardial infarction, inhibition of COX-2 decreased myocyte cross-sectional area, an index of hypertrophy (19). In addition to regulation of protein synthesis, PGE 2 also stimulated synthesis and secretion of atrial natriuretic peptide (ANP) (10) and ANP promoter activity in myocytes (27); however, no signaling mechanisms were identified in those studies.…”

Spontaneous Development of Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthases

“…Quantitative real-time PCR was performed with a QuantiTect Probe PCR kit (Quiagen). 15 Fluorescence resonance energy transfer probes and primers were purchased from Applied Biosystems (Foster City, CA, USA).…”