Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin (PG) formation by targeting cyclooxygenase (COX) 1 and 2. Long-term use of NSAIDs that selectively inhibit COX2 increases the risk for thrombotic events, cardiac failure, and hypertension. However, the underlying mechanisms remain unclear. In this study, COX1- and COX2-deficient rats were created via Cas9/RNA-mediated gene targeting. DNA genotyping and Western blot analysis confirmed successful generation of COX1and COX2 rats. Adult COX1 rats grew normally, while more than 70% of COX2 rats after wean died within 2 months. Echocardiography showed markedly reduced left ventricular ejection fraction and fractional shortening in adult COX2 rats compared to those in wildtype (WT) controls. Histological analysis revealed accumulation of inflammatory cells and severe interstitial and perivascular fibrosis in COX2 cardiac tissues. Moreover, cardiac ATP and acetyl-CoA production was dramatically decreased in COX2 rats. Consistently, the expression of genes related to mitochondrial oxidation, such as those that encode for subunits of pyruvate dehydrogenase complex and acyl CoA dehydrogenases, were downregulated, while glycolytic hexokinase 1 (HK1) was upregulated in COX2 heart tissues. These observations indicate that COX2-deficient rats developed spontaneously heart failure, likely as a result of dysregulated cardiac energy metabolism.
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