Disruption of hedgehog signalling in ApoE-/- mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages
Disruption of hedgehog signalling in ApoE-/- mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages
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DOI：
10.1002/path.2193
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发表时间：
2007-08-01
影响因子：
7.3
通讯作者：
Lutgens, E.
中科院分区：
文献类型：
--
作者：
Beckers, L.;Heeneman, S.;Lutgens, E.
胚胎通路经常在成人病理学中重新表达。在这里，我们研究了形态形成因子Hedgehog(HH)的作用，我们发现它在动脉粥样硬化斑块中重新表达。雄性ApoE-/-小鼠从6周龄或18周龄开始用抗HH抗体(5E1)或对照免疫球蛋白(1E6)治疗12周。抑制HH信号导致主动脉弓内斑块总面积显著增加，这是晚期斑块(动脉粥样硬化)面积增加(分别为54%和36%)的结果。在接受抗-HH治疗的小鼠中，斑块中含有大的(18-35%)、充满脂质的、有时是多核的巨噬泡沫细胞。抗HH治疗后血浆胆固醇水平下降。在骨髓来源的巨噬细胞中，抑制HH信号后泡沫细胞的形成得到促进。抗HH治疗导致早期oxLDL摄取增加54-75%(10-240分钟)，这是清道夫受体介导的。在oxLDL孵育3-24小时后，这些巨噬细胞经抗HH处理后，油红0染色加深，胆固醇酯增多。重组Shh激活HH信号级联导致oxLDL摄取减少。在这里，我们表明，HH信号通路是调节血脂水平和动脉粥样硬化发生发展的形态发生通路之一。版权所有(C)2007年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Embryonic pathways are often re-expressed in adult pathology. Here we investigated the role of the morphogen hedgehog (hh), which we found to be re-expressed in atherosclerotic plaques. Male ApoE-/- mice were treated for 12 weeks with an anti-hh antibody (5E1) or a control IgG (1E6) starting at the age of 6 or 18 weeks. Inhibition of hh signalling induced a significant increase in total plaque area in the aortic arch, a result of an increase (54% and 36%, respectively) in the area of advanced plaques (atheromata). In mice treated with anti-hh, plaques contained large (18-35% > ctrl), lipid-filled, sometimes multinucleated macrophage foam cells. Plasma cholesterol levels decreased after anti-hh treatment. In bone marrow-derived macrophages, foam cell formation was enhanced after inhibition of hh signalling. Anti-hh treatment caused a 54-75% increase in early oxLDL uptake (10-240 min), which was scavenger receptor-mediated. After 3-24 h of oxLDL incubation, intense Oil red 0 staining as well as increased amounts of cholesterol esters were present in these macrophages after anti-hh treatment. Activation of the HH-signalling cascade by recombinant Shh induced a decrease in oxLDL uptake. Here we show that the hh-signalling pathway is one of the morphogenic pathways that regulate plasma lipid levels and atherosclerosis development and progression. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.