Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice.
Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice.
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DOI：
10.1038/srep31130
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发表时间：
2016-08-05
影响因子：
4.6
通讯作者：
Ge R
中科院分区：
文献类型：
--
作者：
Kumar S;Chen M;Li Y;Wong FH;Thiam CW;Hossain MZ;Poh KK;Hirohata S;Ogawa H;Angeli V;Ge R
动脉粥样硬化是一种慢性炎症性疾病，其特征是动脉内壁形成富含脂质的斑块。ADAMTS4(一种具有血栓反应蛋白4基序的去整合素和金属蛋白酶)是一种分泌型蛋白水解酶，调节动脉壁和动脉粥样硬化斑块的代谢。最近的报道表明，在人类动脉粥样硬化斑块和急性冠脉综合征患者的血浆中，ADAMTS4水平升高。然而，ADAMTS4增加是动脉粥样硬化的结果，还是ADAMTS4在动脉粥样硬化形成中起因果作用尚不清楚。在这项工作中，我们利用载脂蛋白E缺陷(ApoE−/−)和Adamts4基因敲除的小鼠，研究了ADAMTS4在饮食诱导的动脉粥样硬化中的作用。我们发现，在载脂蛋白E−/−小鼠中，随着动脉粥样硬化的进展，ADAMTS4在斑块中的表达增加。APOE−/−Adams 4−/−双基因敲除小鼠在18周龄时表现出显著的斑块负荷减少。ADAMTS4的缺失导致斑块表型更加稳定，斑块易损性指数显著降低，其特征是脂质含量减少，巨噬细胞伴随着平滑肌细胞、胶原沉积和纤维化帽厚度的显著增加。动脉粥样硬化的减轻伴随着血浆炎症细胞因子谱的改变。这些结果首次证明ADAMTS4在饮食诱导的载脂蛋白E−/−小鼠动脉粥样硬化中起作用。
Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE−/−) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE−/− mice. ApoE−/−Adamts4−/− double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE−/− mice.