Abstract 1251: Conditional Deletion of Cyclooxygenase -2 in Cardiomyocytes in vivo.
The cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs) derives most plausibly from inhibition of cyclooxygenase (COX) - 2 derived prostacyclin (PGI2). Clinical trials have revealed an increased risk of myocardial infarction and stroke, but also of congestive heart failure in patients taking NSAIDs selective for inhibition of COX-2. While this may reflect NSAID induced hypertension, deletion of the PGI2 receptor results in cardiac injury which persists despite treatment of hypertension. To address the role of COX-2 more directly in the heart, we adopted a cre/lox strategy to generate mice in which COX-2 is conditionally deleted in cardiomyocytes. Exons 6, 7, 8 of COX-2 were flanked by two loxps to generate mice floxed for COX-2. We then pursued cardiomyocyte specific deletion by crossing floxed-COX-2 mice with Mercremer Cre mice. Tamoxifen at 0.1 mg/day/gram of body weight was injected I.P. into ~6 week old male mice for 5 days to activate Cre dependent deletion of COX-2. Contrast MRI was performed to measure the heart function under 1.3% isoflurane and 0.9 L/min oxygen. Deletion of cardiomyocyte COX-2 resulted in a mild congestive heart failure. Two weeks after heart specific COX-2 deletion, left ventricular end systolic volume was increased from 0.017±0.003 to 0.021 ±0.004 cm3 while left ventricular ejection fraction decreased from 65.3±4.6 % to 60.9 ±4.1%; heart rate decreased from 443±24 per minute to 408 ±32 per minute (P<0.05). Interpretation of a recent epidemiological study suggested that sudden cardiac death was an “off target” effect of rofecoxib. However, electrical stimulation of these mice revealed a proarrhythmic phenotype consequent to deletion of cardiomyocyte COX-2. The generation of mice in which COX-2 is subject to inducible deletion permits the study of cell and time specific biology of this enzyme, bypassing the multiple roles of COX-2 in development and early postnatal life which constrain the use of conventional knock out mice. Suppression of COX-2 derived prostanoid formation in cardiomyocytes predisposes mice to cardiac failure and arrhythmogenesis. Both heart failure and sudden cardiac death contribute to the cardiovascular hazard conferred by NSAIDs, particularly those selective for inhibition of COX-2.