Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain

Abstract

Background: Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E2 and in activation of the transcription factor nuclear factor-kappaB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1-/-) or COX-2 (COX-2-/-) was performed.

Results: A majority (>93%) of the differentially expressed genes in both the cortex and hippocampus were altered in one COX isoform knockout mouse but not the other. The major gene function affected in all genotype comparisons was 'transcriptional regulation'. Distinct biologic and metabolic pathways that were altered in COX-/- mice included beta oxidation, methionine metabolism, janus kinase signaling, and GABAergic neurotransmission.

Conclusion: Our findings suggest that COX-1 and COX-2 differentially modulate brain gene expression. Because certain anti-inflammatory and analgesic treatments are based on inhibition of COX activity, the specific alterations observed in this study further our understanding of the relationship of COX-1 and COX-2 with signaling pathways in brain and of the therapeutic and toxicologic consequences of COX inhibition.

Figure 1

β Oxidation gene expression is increased in cerebral cortex of cyclo-oxygenase (COX)-2^-/- mice. The expression of three tandem genes involved in the metabolism of short chain fatty acids to citrate is increased in cerebral cortex of COX-2^-/- mice, as determined by microarray and quantitative PCR (Q-PCR) analysis. These genes, namely hydroxyacyl coenzyme-A dehydrogenase (HADH2), acetyl coenzyme-A acetyltransferase (ACAT1) and ATP citrate lyase, are depicted in the ovals above, along with the enzyme classification (EC) number in parenthesis. Z ratio from the microarray analysis and Q-PCR validation results for each gene are provided below the name of the gene. A positive z ratio represents an increase in expression in COX knockout mice, whereas a negative value denotes a decrease in expression in COX knockout mice. Q-PCR percentage represents the percentage increase in expression over wild-type mice. HADH2 and ACAT1 are expressed in the mitochondria and ATP citrate lyase is expressed in the cytosol. The expression of genes represented as a square is not changed.

Figure 2

Methionine metabolism gene expression is increased in the cerebral cortex of cyclo-oxygenase (COX)-2^-/- mice. The expression of two tandem genes involved in the metabolism of methionine to homocysteine is increased in the cortex of COX-2^-/- mice, as determined by microarray and quantitative PCR (Q-PCR) analysis. These genes, namely methionine adenosyltransferase (MAT2B) and S-adenosylhomocysteine hydrolase (AHCY), are depicted in the ovals above, along with the enzyme classification (EC) number in parenthesis. Z ratio from the microarray analysis and Q-PCR validation results for each gene are provided below the name of the gene. A positive z ratio represents an increase in expression in COX knockout mice, whereas a negative value denotes a decrease in expression in COX knockout mice. Q-PCR percentage represents the percentage increase in expression over wild-type mice.