PGI₂ and TXA₂in vascular injury

Context

Cyclooxygenases participate in the pathogenesis of atherothrombotic lesions by two opposing mechanisms. Platelet cyclooxygenase-1 (COX-1) participates in the synthesis of thromboxane A₂ (TxA₂), a potent vasoconstrictor and platelet activator, and endothelial cyclooxygenase-2 (COX-2) mediates the synthesis of prostacyclin (PGI₂), a vasodilator and platelet inhibitor. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin exert differential effects on platelet-endothelium interactions that are dependent upon their relative capacity to inhibit COX-1 and COX-2 isoenzymes. Potent and sustained inhibition of COX-1 by low dose aspirin provides efficient anti-thrombotic prophylaxis. Different NSAIDs can induce transient and variable inhibition of COX-1-dependent TxA₂ synthesis, and all NSAIDs and COX-2 selective drugs inhibit COX-2 dependent PGI₂ synthesis, but the clinical relevance of both effects is still unclear. These authors explored the role of TxA2/PGI2 balance in the response to vascular injury using TxA₂ and PGI₂ receptor knockout mice.

Significant findings

Catheter-induced vascular injury was enhanced in mice genetically deficient in the PGI₂ receptor, whereas it was depressed in those mice genetically deficient in the TxA₂ receptor or treated with a TxA₂ receptor antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors.

Comments

The results of Cheng et al. are consistent with the well known role of TxA₂ in vascular disease and demonstrate a role in counterbalancing TxA₂ platelet activation for PGI₂ synthesized in response to vascular injury. However, the authors' extrapolation regarding the clinical use of NSAIDs versus COX-2 selective inhibitors is not clear because most NSAIDs lack the potent inhibition and anti-platelet effect provided by aspirin. These data in knockout mice remind us of the need to ensure anti-platelet prophylaxis in patients with cardiovascular disease, particularly before using either NSAIDs or COX inhibitors, but further studies on the potential clinical effects of PGI₂ inhibition by both types of drugs are still warranted.

Methods

Carotid-induced injury, histomorphometric analyses.