Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Abstract

Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the ␣-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.arrhythmia ͉ heart failure ͉ knockout ͉ NSAIDs ͉ fibrosis R andomized, placebo-controlled trials indicate that nonsteroidal antinflammatory drugs (NSAIDs) specific for inhibition of cyclooxygense (COX)-2 confer an increased risk of myocardial infarction and stroke (1-5), effects explicable by suppression of COX-2-derived products, such as prostacyclin (PGI 2 ) and prostaglandia E 2 (PGE 2 ) (6). While, the clinical spectrum of hazard is dominated by a predisposition to thrombosis, an additional feature has been congestive heart failure (1-4). NSAIDs may variably increase blood pressure (7): studies in rodents (8, 9) and a meta-analysis of clinical studies (10) suggest that this reflects inhibition of COX-2 and the specificity with which this is attained (11). Elevation of blood pressure by manipulation of the prostaglandin pathway is conditioned by genetic background in rodents (12). However, given this caveat, deletion or inhibition of COX-2 (8, 13) and deletion of the E prostanoid (EP)-2 receptor (14, 15) or the I-prostanoid receptor (IP) (16) for the COX-2 products, PGE 2 and PGI 2 respectively, may each result in hypertension. Indeed, deletion of the IP in these mice also results in cardiac hypertrophy and fibrosis, effects ameliorated by coincident deletion of the receptor for thromboxane A 2 , the TP, a maneuver that does not, alone, affect blood pressure (16). By contrast, inhibition or deletion of COX-1 attenuates the hypertensive response to infusion of angiotensin II (8) or treatment with a COX-2 inhibitor (13). Although placebo-controlled trials provide unequivocal evidence that COX-2-specific NSAIDs confer a cardiovascular hazard, the number of events within each trial are insufficient to permit analysis of covariates. Thus, it is unknown whether congestive heart failure on NSAIDs results solely from or is exacerbated by hypertension.Although suppression of COX-2-derived prostanoids is sufficient to explain the cardiovascular hazard conferred by purposedesigned and older NSAIDs specific for inhibition of COX-2 (17), there has been interest in the possibility that some or all of these effects might reflect ''off target'' effects. One such example was an overview-trial analysis interpreted to suggest that arrhythmia, cardiac arrest, ...

Nonsteroidal Anti-Inflammatory Drugs and the Heart

“…51 The finding that coxibs and traditional NSAIDs caused a similar increased risk of heart failure indirectly suggests that the high-dose regimens of these agents used in the coxib trials produced comparable levels of vascular COX-2 inhibition.…”

Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice

“…Observational studies consistent with a cardiovascular risk have been reported for several traditional NSAIDs, which also exhibit selectivity for inhibition of COX-2, such as diclofenac and meloxicam (2)(3)(4)(5). The clinically manifest elements of this hazard (a predisposition to thrombotic events, an elevation of blood pressure, cardiac failure, and arrhythmogenesis) have been recapitulated in rodent models in which the COX-2-dependent formation of prostacyclin (PGI 2 ) or its action is disrupted (6)(7)(8). This mechanism would be expected to be influenced by the underlying cardiovascular risk of an individual patient (9).…”

Myocardial Regulation of Lipidomic Flux by Cardiolipin Synthase

“…Thus, these results provide a novel mechanism through which alterations in mitochondrial bioenergetic state can be used to modulate blood flow and hence substrate delivery. Moreover, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids have profound effects on cardiovascular hemodynamic function and ion channel kinetics (75,76).…”