Congestive heart failure in COX2 deficient rats

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Metabolic Disease

Background:

• Non-steroidal anti-inflammatory drugs (NSAIDs) targeting cyclooxygenase (COX) enzymes are widely used.
• Selective COX2 inhibitors are linked to increased thrombotic events, cardiac failure, and hypertension, but mechanisms are unclear.

Purpose of the Study:

• To investigate the role of cyclooxygenase-2 (COX2) in cardiac function and metabolism.
• To elucidate the mechanisms underlying potential cardiac dysfunction in COX2-deficient models.

Main Methods:

• Generation of COX1- and COX2-deficient rats using CRISPR/Cas9 gene targeting.
• Confirmation of genetic modifications via DNA genotyping and Western blot.
• Assessment of cardiac function using echocardiography and histological analysis.
• Analysis of cardiac energy metabolism, including ATP, acetyl-CoA production, and gene expression related to mitochondrial oxidation and glycolysis.

Main Results:

• COX1-deficient rats exhibited normal growth, while COX2-deficient rats showed high mortality post-weaning.
• COX2-deficient rats displayed significantly reduced left ventricular ejection fraction and fractional shortening.
• Histological examination revealed cardiac inflammation and fibrosis in COX2-deficient rats.
• Cardiac ATP and acetyl-CoA production were markedly decreased in COX2-deficient rats, with altered expression of genes involved in mitochondrial oxidation and glycolysis.

Conclusions:

• COX2 deficiency leads to spontaneous heart failure in rats.
• Dysregulated cardiac energy metabolism, characterized by impaired mitochondrial oxidation and altered glycolysis, is a key factor in COX2-deficient heart failure.
• These findings suggest a critical role for COX2 in maintaining cardiac metabolic homeostasis and function.