Loss of the lysophosphatidylcholine effector, G2A, ameliorates aortic atherosclerosis in low-density lipoprotein receptor knockout mice
Loss of the lysophosphatidylcholine effector, G2A, ameliorates aortic atherosclerosis in low-density lipoprotein receptor knockout mice
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DOI：
10.1161/01.atv.0000246774.02426.71
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发表时间：
2006-12-01
影响因子：
8.7
通讯作者：
Kabarowski, Janusz H. S.
中科院分区：
文献类型：
--
作者：
Parks, Brian W.;Lusis, Aldons J.;Kabarowski, Janusz H. S.
溶血磷脂酰胆碱是动脉粥样硬化病变中低密度脂蛋白（LDL）氧化和分泌型磷脂酶A（2）介导的脂质水解的主要产物。G2 A受体介导培养的巨噬细胞和T细胞对溶血磷脂酰胆碱的趋化性，支持该受体在体内的促动脉粥样硬化作用。我们研究了G2 A调节小鼠动脉粥样硬化的能力。方法和结果-我们测量了G2 A（+/+）和G2 A（-/-）LDL受体敲除（LDLR-/-）小鼠的动脉粥样硬化。与先前的研究一致，主动脉窦的早期病变大小不受G2 A缺乏的影响。然而，G2 A缺乏减弱了该部位的病变进展（平均病变面积减少42%至44%），并在短期和长期饮食干预后导致整个主动脉粥样硬化的强力抑制（主动脉病变覆盖率减少：9周时为62%至73%，20周时为75%至84%）。在G2 A（-/-）LDLR-/-小鼠中，在对T细胞募集无任何可检测影响的情况下，主动脉易病变部位的内膜巨噬细胞蓄积显著减少。脂蛋白谱检查显示，在长时间的饮食干预后，与G2 A（-/-）LDLR-/-小鼠相比，G2 A（-/-）LDLR-/-小鼠的循环高密度脂蛋白（HDL）胆固醇水平升高（平均HDL胆固醇浓度增加54%）。体内致动脉粥样硬化刺激与其趋化作用一致，但多效性效应，包括脂蛋白代谢的调节，也可能有贡献。
Objective - Lysophosphatidylcholine is a major product of low-density lipoprotein (LDL) oxidation and secretory phospholipase A(2)-mediated lipid hydrolysis within atherosclerotic lesions. The G2A receptor mediates chemotaxis of cultured macrophages and T cells to lysophosphatidylcholine, supporting a pro-atherogenic role for this receptor in vivo. We investigated the ability of G2A to modulate atherosclerosis in mice.Methods and Results - We measured atherosclerosis in G2A(+/+) and G2A(-/-) LDL receptor knockout (LDLR-/-) mice. Consistent with a previous study, early lesion size at the aortic sinus was unaffected by G2A deficiency. However, G2A deficiency attenuated lesion progression at this site (42% to 44% reduction in average lesion area) and led to robust suppression of atherosclerosis throughout the aorta after short and extended periods of diet intervention ( reduction in aortic lesion coverage: 62% to 73% at 9 weeks, 75% to 84% at 20 weeks). In G2A(-/-) LDLR-/- mice, intimal macrophage accumulation at lesion-prone sites of the aorta was significantly reduced in the absence of any detectable effect on T cell recruitment. Examination of lipoprotein profiles revealed elevated levels of circulating high-density lipoprotein (HDL) cholesterol in G2A(-/-) LDLR-/- mice compared with their G2A(-/-) LDLR-/- counterparts after extended periods of diet intervention (54% increase in mean HDL cholesterol concentration).Conclusion - G2A provides a pro-atherogenic stimulus in vivo consistent with its chemotactic action but to which a pleiotropy of effects, including modulation of lipoprotein metabolism, may also contribute.