Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

Ron M.A Heeren,H Maxime Lagraauw,Martine Bot,Erik A.L Biessen,Ilze Bot,Luke Macaleese,Johan Kuiper,Theo J.C Van Berkel,Paul H.A Quax,Saskia C.A De Jager

doi:10.1194/jlr.m032862

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.

Highlights

Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque
We previously demonstrated that systemic mast cell activation during atherogenesis leads to increased plaque progression in apoE deficient mice [6], while others show that the absence of mast cells, and in particular mast cell-derived interleukin (IL)-6 and interferon (IFN)-␥, attenuated atherosclerotic lesion development in low-density lipoprotein receptor-deficient (LDLrϪ/Ϫ) mice [7]
The LPA assigned peaks detected in secondary ion mass spectrometry (SIMS) imaging analysis of plaque lysates are identical to m/z values obtained by LC/MS spectroscopy, providing an orthogonal validation of the SIMS results

Summary

Introduction

Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. 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. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. Bot. Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation. We previously demonstrated that systemic mast cell activation during atherogenesis leads to increased plaque progression in apoE deficient mice [6], while others show that the absence of mast cells, and in particular mast cell-derived interleukin (IL)-6 and interferon (IFN)-␥, attenuated atherosclerotic lesion development in low-density lipoprotein receptor-deficient (LDLrϪ/Ϫ) mice [7]. Focal activation of mast cells in the adventitia of advanced carotid artery plaques promoted macrophage apoptosis, microvascular leakage, de novo leukocyte influx, and the incidence of intraplaque hemorrhage. It is worth noting that LPA progressively accumulates in human and mouse atherosclerotic plaques [20, 21], and was shown to be involved in atherogenesis by virtue of its pro-coagulating capacity [20, 22] and its endothelial/leukocyte interaction [23, 24]

Methods

Results

Conclusion