Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure

Article

关键词: IDIOPATHIC DILATED CARDIOMYOPATHY;    MATRIX-METALLOPROTEINASE ACTIVITY;    FAILING HUMAN HEART;    UP-REGULATION;    INFLAMMATION;    EXPRESSION;    DYSFUNCTION;    MYOCARDITIS;    ACTIVATION;    INDUCTION;   

DOI  :  10.1161/01.CIR.0000121354.34067.48

来源: SCIE

【 摘 要 】

Background - Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression. Methods and Results - Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg . kg(-1) . wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor - containing mice chow (n = 50) or plain mice chow (controls; n = 50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography ( with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor - treated mice decreased significantly less than in control mice (9% versus 29%, P < 0.01). Mortality was significantly lower for COX-2 inhibitor - treated mice than for control mice (18% versus 38%, P < 0.01). These results were confirmed in a revalidation study in COX-2 inhibitor - treated mice ( n = 25) and controls ( n = 25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor - treated mice but showed more extensive signs of cardiomyopathy ( as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442 +/- 1635 versus 4300 +/- 2408 arbitrary units, P < 0.022]). Conclusions - COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.

【 授权许可】

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