Secretory phospholipase A(2) modified HDL rapidly and potently suppresses platelet activation

Levels of secretory phospholipases A(2) (sPLA(2)) highly increase under acute and chronic inflammatory conditions. sPLA(2) is mainly associated with high-density lipoproteins (HDL) and generates bioactive lysophospholipids implicated in acute and chronic inflammatory processes. Unexpectedly, pharmacological inhibition of sPLA(2) in patients with acute coronary syndrome was associated with an increased risk of myocardial infarction and stroke. Given that platelets are key players in thrombosis and inflammation, we hypothesized that sPLA(2)-induced hydrolysis of HDL-associated phospholipids (sPLA(2)-HDL) generates modified HDL particles that affect platelet function. We observed that sPLA(2)-HDL potently and rapidly inhibited platelet aggregation induced by several agonists, P-selectin expression, GPIIb/IIIa activation and superoxide production, whereas native HDL showed little effects. sPLA(2)-HDL suppressed the agonist-induced rise of intracellular Ca(2+) levels and phosphorylation of Akt and ERK1/2, which trigger key steps in promoting platelet activation. Importantly, sPLA(2) in the absence of HDL showed no effects, whereas enrichment of HDL with lysophosphatidylcholines containing saturated fatty acids (the main sPLA(2) products) mimicked sPLA(2)-HDL activities. Our findings suggest that sPLA(2) generates lysophosphatidylcholine-enriched HDL particles that modulate platelet function under inflammatory conditions.