Circulating Platelet-Activating Factor Is Primarily Cleared by Transport, Not Intravascular Hydrolysis by Lipoprotein-Associated Phospholipase A 2 / PAF Acetylhydrolase

Abstract

The phospholipid platelet-activating factor (PAF) stimulates all cells of the innate immune system and numerous cardiovascular cells. A single enzyme (plasma PAF acetylhydrolase [PAF-AH] or lipoprotein-associated phospholipase [Lp-PL]A(2)) in plasma hydrolyzes PAF, but significant controversy exists whether its action is pro- or antiinflammatory and accordingly whether its inhibition will slow cardiovascular disease. We sought to define how PAF and related short-chain oxidized phospholipids turnover in vivo and the role of PAF acetylhydrolase/Lp-PLA(2) in this process. [(3)H-acetyl]PAF was hydrolyzed by murine or human plasma (t(1/2), 3 and 7 minutes, respectively), but injected [(3)H-acetyl]PAF disappeared from murine circulation more quickly (t(1/2), <30 seconds). [(3)H]PAF clearance was unchanged in PAF receptor(-/-) animals, or over the first 2 half-lives in PAF-AH(-/-) animals. [(3)H]PAF turnover was reduced by coinjecting excess unlabeled PAF or an oxidatively truncated phospholipid, and [(3)H]PAF clearance was slowed in hyperlipidemic apolipoprotein (apo)E(-/-) mice with excess circulating oxidatively truncated phospholipids. [(3)H]PAF, fluorescent NBD-PAF, or fluorescent oxidatively truncated phospholipid were primarily accumulated by liver and lung, and were transported into endothelium as intact phospholipids through a common mechanism involving TMEM30a. Circulating PAF and oxidized phospholipids are continually and rapidly cleared, and hence continually and rapidly produced. Saturable PAF receptor-independent transport, rather than just intravascular hydrolysis, controls circulating inflammatory and proapoptotic oxidized phospholipid mediators. Intravascular PAF has access to intracellular compartments. Inflammatory and proapoptotic phospholipids may accumulate in the circulation as transport is overwhelmed by substrates in hyperlipidemia.