Ruolo della fosfolipasi A2 secretoria e della fosfolipasi associata alle lipoproteine nel rischio cardiovascolare

Phospholipase A2(PLA2) are enzymes that hydrolyze the ester bond of glycerophospholipids releasing free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. PLA2are present in the atherosclerotic plaques and their direct involvement in the proatherogenic inflammatory response is well documented. Epidemiological and genetic studies have demonstrated the correlation of the PLA2 mass and enzymatic activity with the incidence of cardiovascular diseases. The potential pro-atherogenic role of PLA2led to the development of two small molecules, varespladib, a reversible sPLA2 inhibitor, and darapladib, a selective Lp-PLA2inhibitor. Both molecules have demonstrated antiatherosclerotic properties in animal models, and positive effects on atherosclerotic plaque composition evaluated in phase 2 clinical trials. On these grounds, the results of three phase 3 studies have recently been published: the VISTA-16 study with varespladib in patients with acute coronary syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in patients with stable coronary heart disease and acute coronary syndrome, respectively. Unexpectedly, both studies did not demonstrate an additional protective action of PLA2inhibitors over the standard of care treatment with statins, antiplatelet drugs, and coronary revascularization.In the present article, the enzymatic properties and the involvement of sPLA2 and Lp-PLA2in atherogenesis are reviewed, with a focus on the results of experimental studies and clinical studies with both varespladib and darapladib inhibitors.