Congestive heart failure in COX2 deficient rats

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 COX1 −/− and 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.