Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size
Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size
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DOI：
10.1161/01.atv.0000203503.82693.c1
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发表时间：
2006-03-01
影响因子：
8.7
通讯作者：
Terkeltaub, R
中科院分区：
文献类型：
--
作者：
Boisvert, WA;Rose, DM;Terkeltaub, R
目的-转谷氨酰胺酶2 （TG2）是一种广泛表达的蛋白质交联、伤口愈合和组织纤维化调节剂，可介导巨噬细胞对凋亡细胞的摄取和转化生长因子- β的释放，从而限制白细胞介导的炎症。在动脉粥样硬化中，氧化应激和未酯化胆固醇的积累刺激动脉粥样硬化病变细胞凋亡。晚期动脉粥样硬化病变中的细胞死亡促进病变扩张和易损斑块容易破裂。因此，我们验证了白细胞TG2表达限制动脉粥样硬化的假设。方法和结果-我们将TG2-/-或TG2+/+骨髓移植到致命照射的低密度脂蛋白受体(LDLR)-/-小鼠中，并在16周后评估饮食诱导的动脉粥样硬化。随后，我们研究了培养的TG2-/-和同源TG2+/+小鼠巨噬细胞对动脉粥样硬化的调节功能。与TG2+/+骨髓受体相比，LDLR-/-受体的动脉粥样硬化性主动脉瓣病变更大，内膜下巨噬细胞渗透更多。病变内膜TG2表达在TG2+/+骨髓受体中表现强劲，而在TG2-/-骨髓受体中表现不佳。培养的TG2-/-巨噬细胞表现出凋亡白细胞的吞噬作用减弱，内吞作用不变，氧化LDL降解，但维甲酸诱导的胆固醇逆向转运和凋亡细胞摄取介质ABCA1减弱。结论-我们得出巨噬细胞TG2的表达在体外促进凋亡细胞清除和ABCA1的表达，并限制体内动脉粥样硬化病变的大小。
Objective - Transglutaminase 2 ( TG2), a broadly expressed regulator of protein cross-linking, wound healing, and tissue fibrosis, mediates apoptotic cell ingestion and transforming growth factor-beta release by macrophages and thereby can limit leukocyte-mediated inflammation. In atherosclerosis, oxidative stress and accumulation of unesterified cholesterol stimulate atherosclerotic lesion cell apoptosis. Cell death in advanced atherosclerotic lesions promotes lesion expansion and vulnerable plaques prone to rupture. Hence, we tested the hypothesis that leukocyte TG2 expression limits atherosclerosis.Methods and Results - We transplanted TG2-/- or TG2+/+ bone marrow into lethally irradiated low-density lipoprotein receptor ( LDLR)-/- mice and evaluated diet-induced atherosclerosis after 16 weeks. We subsequently studied cultured TG2-/- and congenic TG2+/+ mouse macrophages for selected atherogenesis regulatory functions. Atherosclerotic aortic valve lesions in LDLR-/- recipients of TG2-/- bone marrow were larger and more subintimal lesional macrophage penetration than in TG2+/+ marrow recipients. Lesion intimal TG2 expression appeared robust in TG2+/+ but not TG2-/- marrow recipients. Cultured TG2-/- macrophages demonstrated diminished phagocytosis of apoptotic leukocytes, unaltered endocytosis, and degradation of oxidized LDL but decreased retinoic acid induction of the reverse cholesterol transport and apoptotic cell uptake mediator ABCA1.Conclusions - We conclude that macrophage TG2 expression promotes both apoptotic cell clearance and ABCA1 expression in vitro and limits atherosclerotic lesion size in vivo.