Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure

Abstract

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 Ϫ1 · wk Ϫ1 for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor-containing mice chow (nϭ50) or plain mice chow (controls; nϭ50). 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%, PϽ0.01). Mortality was significantly lower for COX-2 inhibitor-treated mice than for control mice (18% versus 38%, PϽ0.01). These results were confirmed in a revalidation study in COX-2 inhibitor-treated mice (nϭ25) and controls (nϭ25). 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 [6442Ϯ1635 versus 4300Ϯ2408 arbitrary units, PϽ0.022]). Conclusions-COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

“…On the other hand, it is known that DOX induces myocardial expression cyclooxygenase-2, 38 which occupies a central position in the biosynthesis of proinflammatory prostaglandin E2, prostacyclin and thromboxane A 2 , and that inhibition of cyclooxygenase-2 improves cardiac function in DOX-induced cardiomyopathy. 39 Actually, we noted that DOX strongly induced myocardial cyclooxygenase-2 expression in the present study and that this effect was largely inhibited by G-CSF. However, we also found that inhibition of cyclooxygenase-2 by a specific cyclooxygenase-2 inhibitor could not mimic the effect of G-CSF on DOX-induced cardiomyopathy: no improvement in cardiac function or no restoration of cardiomyocyte size, though with partial reduction in myocardial inflammation and fibrosis.…”

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.…”

Transcriptional Control of COX-2 via C/EBPβ

“…25 By contrast, COX-2 has been implicated to mediate postischemic myocardial infarction and heart failure. 26,27 Taken together, the experimental data and clinical findings indicate that COX-2 may be a friend or a foe of vascular integrity, depending on the cell types wherein its expression is induced, the downstream enzymes with which it is coupled, and the relative quantities of protective and damaging prostanoids that it generates. 28 The complex roles that COX-2 plays in cardiovascular physiology and diseases may explain the disparity between clinical studies and animal experiments.…”