Clopidogrel binds to lp-pla2 and inhibits the enzyme activity. A new pleiotropic effect of this antiplatelet drug?

M.E. Tsoumani, C.C. Tellis, M.V. Chatziathanasiadou, A.N. Katsikoudi, V.G. Kontogianni, A.G. Tzakos, A.D. Tselepis



Lipoprotein Phospholipase A2 (Lp-PLA2) circulates in plasma in active form bound to various lipoproteins, primarily to LDL and in a smaller proportion to HDL. Lp-PLA2 catalyzes the hydrolysis of platelet activating factor (PAF) and oxidized phospholipids. These phospholipids are formed during oxidative modification of LDL in the arterial intima and may play important role in the pathophysiology of atherosclerosis. Many clinical studies have demonstrated that elevated Lp-PLA2 levels in plasma are correlated with increased cardiovascular risk. Clopidogrel as antiplatelet therapy is still one of the drugs of choice for cardiovascular patients. Apart from potent antiplatelet activity, clopidogrel exhibits various pleiotropic effects. We investigated the possible interaction of clopidogrel with Lp-PLA2 as well as the effect of clopidogrel on the activity of Lp-PLA2, in vitro. Using fluoroscence spectroscopy, we observed that clopidogrel binds to recombinant Lp-PLA2 (rLp-PLA2). The effect of clopidogrel on rLp-PLA2 as well as on the enzyme activity in total plasma, and on LDL was determined by the trichloroacetic acid precipitation method using [3H] PAF as a substrate. Clopidogrel inhibits the enzymatic activity of rLp-PLA2, LDL and plasma Lp-PLA2 activity in a dose-dependent manner. However, according to the results obtained by LC/MS-MS, clopidogrel is not degraded by Lp-PLA2, since the spectrum of clopidogrel MRM (m / z 322) was the same either in the presence or absence of Lp-PLA2. In conclusion, clopidogrel binds to Lp-PLA2 and inhibits the enzyme activity of Lp-PLA2, suggesting a new pleiotropic (antiatherogenic) effect of clopidogrel.

Keywords: Lp-PLA2, clopidogrel, atherosclerosis, pleiotropic effect