Congestive heart failure in COX2 deficient rats
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Qiangyou Wan , Deping Kong , Qian Liu , Shumin Guo , Chenchen Wang , Yan Zhao , 1* 2* Zun-Ji Ke & Ying Yu 1
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Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology; Key Laboratory of Immune Microenvironment and
Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China Received May 15, 2020; accepted August 7, 2020; published online September 14, 2020
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 dra−/− matically 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. NSAID, cyclooxygenase, prostaglandin, heart failure, energy metabolism Citation:
Wan, Q., Kong, D., Liu, Q., Guo, S., Wang, C., Zhao, Y., Ke, Z.J., and Yu, Y. (2020). Congestive heart failure in COX2 deficient rats. Sci China Life Sci 63, https://doi.org/10.1007/s11427-020-1792-5
INTROUDUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation, reduce fever, and relieve chronic pain, such as in rheumatoid arthritis. NSAIDs act by suppressing cyclooxygenase (COX)-derived production of prostaglandins (PGs). There are two isoforms of COX enzymes: constitutively expressed COX1 and inducible COX2. NSAIDs that are specific for
*Corresponding authors (Zun-Ji Ke, email: [email protected]; Ying Yu, email: [email protected])
COX2 inhibition greatly decrease gastrointestinal com
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