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Published on: January 21, 2018
Cyclooxygenase-2 inhibitor treatment improves left ventricular function and mortality in a murine model of
Reynolds M Delgado1, Mohamad A Nawar, Aly M Zewail
1Department of Adult Cardiology, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Tex 77030, USA. rdelgado@pol.net
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.
Insights
Cyclooxygenase-2 (COX-2) inhibitors attenuated heart failure progression in mice. This study found COX-2 inhibition reduced cardiac dysfunction and mortality in a doxorubicin-induced heart failure model.
Area of Science:
- Cardiovascular Research
- Inflammation and Immunology
- Pharmacology
Background:
- Heart failure progression post-myocardial injury involves inflammatory mediators like cyclooxygenase-2 (COX-2).
- COX-2 inhibitors are established treatments for inflammation-mediated diseases.
Purpose of the Study:
- To investigate if COX-2 inhibition can mitigate the progression of heart failure.
- To assess the therapeutic potential of COX-2 inhibitors in a murine model of heart failure.
Main Methods:
- Doxorubicin-induced heart failure in 100 mice, with treatment groups receiving COX-2 inhibitors or placebo.
- Left ventricular ejection fraction assessed via transthoracic echocardiography with intravascular ultrasound.
- Pathological analysis and COX-2 protein levels determined by immunoblotting.
Main Results:
- COX-2 inhibitor treatment significantly reduced the decrease in left ventricular ejection fraction (9% vs. 29%).
- Mortality rates were significantly lower in the COX-2 inhibitor group (18% vs. 38%).
- Hearts from control mice showed more cardiomyopathy and higher COX-2 protein levels.
Conclusions:
- COX-2 inhibitors effectively attenuate the progression of doxorubicin-induced heart failure in mice.
- Targeting COX-2 represents a viable strategy to manage post-injury cardiac dysfunction.
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