Abstract
To explore the effects of celecoxib on pressure overload-induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body-weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib-induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF-κB pathway and inhibition of oxidative stress via increases in nuclear factor E2-related factor-2-mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload-induced CH by reducing apoptosis, inflammation and oxidative stress.
Highlights
Hypertrophic remodelling characterized by enlarged cardiomyocytes and increase in heart size is an adaptation to stress, especially due to pressure overload
Celecoxib increased survival rates of rats with cardiac hypertrophy (CH) independent of suppressing hypertension Cardiac hypertrophy rats were stratified into groups to be treated with or without celecoxib for either 2 or 4 weeks
Because CH is associated with cardiac fibrosis, we examined the fibrotic effect of CH on the heart by Sirius-red staining for collagen a 2015 The Authors
Summary
Hypertrophic remodelling characterized by enlarged cardiomyocytes and increase in heart size is an adaptation to stress, especially due to pressure overload. Hypertrophy is the leading cause of various cardiovascular diseases, including hypertension, myocardial infarction, valvular disease and cardiomyopathy [1,2,3]. Pressure overload-induced cardiac apoptosis is the initial pathogenic characteristic of CH and remodelling [4]. Mature cardiomyocytes are terminally differentiated; they lack regenerative capacity [5,6,7]. Necrotic cells are replaced by the extracellular matrix (ECM) which impairs myocardial contractility, increases interstitial fibrosis, promotes CH, and leads to heart failure [8,9,10]. Research suggests that cardiac inflammatory mediators expressed in response to pressure overload induces deleterious a 2015 The Authors
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