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.