Thromboxane

Abstract: Dietary fats play a critical role in atherogenesis and thrombosis. Both the amount of fat consumed and its composition affect various events associated with coronary artery disease. Dietary unsaturated fatty acids appear to reduce the incidence of these events, in particular polyunsaturated fatty acids (PUFAs), which exert markedly different effects on risk factors related to heart disease. The omega-3 (n-3) PUFAs, at high levels of dietary intake, significantly reduce hyperlipidemia and the production of the prothrombotic substance thromboxane, and they enhance the production of the platelet-antiaggregatory substance prostacyclin. Data from clinical trials indicate a significant reduction of levels of very low density lipoprotein (VLDL). The n-3 PUFAs also depress hepatic fatty acid and triglyceride synthesis and VLDL secretion. The n-3 PUFAs of fish oils displace arachidonic acid from tissue phospholipids and concomitantly increase n-3 PUFA levels, which inhibit thromboxane synthesis. Most significantly, in human subjects the antiaggregatory prostacyclin PGI3 is also synthesized and the net effect is enhanced antiaggregatory/antiadhesive activity. In addition, the chemotactic platelet adhesion-promoting substance leukotriene B4 is suppressed. These composite effects reduce atherogenesis and thrombosis. Fish oil n-3 PUFAs may also reduce blood pressure and blood viscosity. Through the combined vasodilatory effects via prostacyclin (PGI2 and PGI3), fish oils may improve peripheral circulation and thereby facilitate VLDL removal. The n-3 PUFAs of fish oils, by altering membrane fluidity in a specific manner, alter the activities of membrane-bound enzymes and may change receptor activity, specificity and signal transduction. Overall, these data indicate a beneficial role for n-3 PUFAs as part of a dietary approach to minimizing coronary artery disease.

Abstract: Systemic inflammation has been shown to be a contributing factor to the instability of atherosclerotic plaques in patients with acute coronary syndromes (ACS). VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI). The role of p38 MAPK in platelet aggregation of normal individuals was examined using the selective second generation p38 MAPK inhibitor VX-702. Treatment of platelets with thrombin (activates PAR1 and PAR4 thrombin receptors), SFLLRN (PAR1), AYPGKF (PAR4), collagen (alpha2beta1 and GPVI/FCgammaIIR receptors) and U46619 (TXA(2)) resulted in strong activation of p38 MAPK. Activation of the GPIb von Willebrand factor receptor with ristocetin did not stimulate p38 MAPK. Pre-treatment of platelets with 1 microM VX-702 completely inhibited activation of p38 MAPK by thrombin, SFLLRN, AYPGKF, U46619, and collagen. There was no effect of VX-702 on platelet aggregation induced by any of the agonists in the presence or absence of aspirin, heparin or apyrase. It has been postulated that a potential role of p38 MAPK is to activate phospholipase A(2) (cPLA(2)) which catalyses formation of arachidonic acid leading to production of thromboxane. Interestingly, we show contrasting effects of p38 MAPK inhibition as compared to aspirin inhibition on platelet aggregation in response to collagen. Blockade of TXA(2) production by aspirin results in significant inhibition of collagen activation. However,VX-702 has no effect on collagen-mediated platelet aggregation, suggesting that blocking p38 MAPK does not effect thromboxane production in human platelets. Therefore, unlike aspirin blockade of thromboxane production in platelets, p38 MAPK inhibitors such as VX-702 do not significantly affect platelet function and would not be expected to contribute to an elevated risk of bleeding side-effects in treated patients.