Abstract
Levels of secretory phospholipases A2 (sPLA2) highly increase under acute and chronic inflammatory conditions. sPLA2 is mainly associated with high-density lipoproteins (HDL) and generates bioactive lysophospholipids implicated in acute and chronic inflammatory processes. Unexpectedly, pharmacological inhibition of sPLA2 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 sPLA2-induced hydrolysis of HDL-associated phospholipids (sPLA2-HDL) generates modified HDL particles that affect platelet function. We observed that sPLA2-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. sPLA2-HDL suppressed the agonist-induced rise of intracellular Ca2+ levels and phosphorylation of Akt and ERK1/2, which trigger key steps in promoting platelet activation. Importantly, sPLA2 in the absence of HDL showed no effects, whereas enrichment of HDL with lysophosphatidylcholines containing saturated fatty acids (the main sPLA2 products) mimicked sPLA2-HDL activities. Our findings suggest that sPLA2 generates lysophosphatidylcholine-enriched HDL particles that modulate platelet function under inflammatory conditions.
Highlights
Secretory phospholipases A2 are members of the phospholipase A2 family of enzymes which hydrolyze the sn-2 ester bond in phospholipids, generating nonesterified free fatty acids and lysophospholipids
To test whether secretory phospholipases A2 (sPLA2)-high-density lipoprotein (HDL) affects platelet aggregation, platelets isolated from plasma of healthy donors were exposed to different agonists including ADP, collagen and thrombin in the presence or absence of native HDL and sPLA2-HDL
We found that HDL isolated by dextran-sulfate precipitation inhibited platelet activation after sPLA2-mediated modification (Supplementary Figure 3), whereas native HDL showed no effect
Summary
Secretory phospholipases A2 (sPLA2) are members of the phospholipase A2 family of enzymes which hydrolyze the sn-2 ester bond in phospholipids, generating nonesterified free fatty acids and lysophospholipids. Under acute inflammatory conditions sPLA2-IIA is mainly associated with high-density lipoprotein (HDL), the principal plasma carrier of phospholipids and the major substrate for sPLA212, 13. Accumulating evidence suggests that inflammatory responses are linked to increased platelet activation in the bloodstream of patients with systemic inflammation and sepsis[19]. Pharmacological inhibition of sPLA2 resulted in increased incidence of myocardial infarction and stroke[7], raising the possibility that increased sPLA2 activity during inflammation might modulate platelet activity. Based on these observations, we tested whether sPLA2-induced hydrolysis of HDL-associated phospholipids generates particles that affect platelet functionality. Our findings suggest sPLA2-modified HDL particles potently suppress agonist induced platelet activation
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