title: Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation.
abstract: Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, 2333 CC, Leiden University, Leiden, The Netherlands.
authors: Martine
authors: M
authors: Bot
authors: Saskia C A
authors: SC
authors: de Jager
authors: Luke
authors: L
authors: MacAleese
authors: H Maxime
authors: HM
authors: Lagraauw
authors: Theo J C
authors: TJ
authors: van Berkel
authors: Paul H A
authors: PH
authors: Quax
authors: Johan
authors: J
authors: Kuiper
authors: Ron M A
authors: RM
authors: Heeren
authors: Erik A L
authors: EA
authors: Biessen
authors: Ilze
authors: I
authors: Bot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004205:Cromolyn Sodium / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D011859:Radiography; D053802:Tryptases / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D053802:Tryptases; C032881:lysophosphatidic acid; D004205:Cromolyn Sodium
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