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

Abstract

Atherosclerotic plaque rupture is a leading cause of acute coronary syndromes, such as unstable angina and myocardial infarction ( 1 ). Infl ammatory cells are regarded as key players in the pathogenesis of plaque rupture ( 2, 3 ), and the mast cell, a potent infl ammatory cell, has been shown to accumulate in the rupture-prone shoulder region of human atheromas ( 4 ). Activated mast cells have been identifi ed in the adventitia of vulnerable and ruptured lesions in patients with myocardial infarction, and more importantly, their numbers and degree of activation were found to correlate with the incidence of plaque rupture and erosion ( 5 ). We previously demonstrated that systemic mast cell activation during atherogenesis leads to increased plaque progression in apoE defi cient 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 (LDLr Ϫ / Ϫ ) mice ( 7 ). Moreover, focal activation of mast cells in the adventitia of advanced carotid artery plaques promoted macrophage apoptosis, microvascular leakage, de novo leukocyte infl ux, and the incidence of intraplaque hemorrhage. Mast cell stabilization by cromolyn was seen to prevent these pathophysiological events ( 6 ).Various pathways of mast cell activation have been demonstrated such as cross-linking of the high-affi nity 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 LPAmediated 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 defi cient 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. Press, February 10, 2013 DOI 10.1194 Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular infl ammation Abbreviations: apoE Ϫ / Ϫ , apolipoprotein E-defi...

Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid

“…It has been reported that LPA promotes hepatocyte secretion of apoBcontaining proteins ( 12 ) and it is possible that some of the changes noted here may be due to changes in plasma LPA levels acting on the liver. Regardless of the mechanism(s) the data presented here further add to the growing body of evidence suggesting that LPA plays a major role in lipid metabolism, infl ammation, and atherosclerosis ( 7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

“…The gene for lipid phosphate phosphatase 3 was identifi ed as a susceptibility locus for coronary artery disease ( 20 ). In mice, LPA was shown to trigger mast cell-driven atherosclerotic plaque destabilization ( 21 ). Thus, there is increasing evidence that LPA plays an important role in vascular pathology and atherosclerosis.…”

Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression

“…In men with hyperlipidemia and in patients with acute cardiovascular disorders [10], plasma IgE levels were shown to be increased as well. Additional in vitro and in vivo evidence has also established a role for complement factors [11,12], neuropeptides [13,14], immune complexes [15] and lipid mediators [16] in mast cell activation during the development and progression of atherosclerosis.…”

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…Remarkably, the tissue content of unsaturated LPA in the small intestine signifi cantly correlated with the extent of aortic atherosclerosis ( 11 ). LPA is emerging as an important signaling molecule in diverse biological processes and disease states , and its role in the pathogenesis of atherosclerosis has been emphasized in recent years (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40).…”