Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid.
Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid.
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DOI：
10.1371/journal.pone.0068197
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kurabayashi M
中科院分区：
文献类型：
--
作者：
Kageyama A;Matsui H;Ohta M;Sambuichi K;Kawano H;Notsu T;Imada K;Yokoyama T;Kurabayashi M
代谢综合征和糖尿病患者体内游离脂肪酸（FFA）水平升高，在动脉粥样硬化性心血管疾病的发生发展中起着重要作用，二十碳五烯酸（EPA）在FFA诱导的血管病变中起着重要作用。虽然血管钙化总是与动脉粥样硬化有关，但其机制尚未完全阐明。在这项研究中，我们测试的假设，EPA阻止成骨细胞分化和矿化的血管平滑肌细胞（VSMC）诱导的棕榈酸（PA），最丰富的长链饱和脂肪酸在血浆中。在人主动脉平滑肌细胞（HASMC）中，PA增加和EPA消除骨相关蛋白基因的表达，包括骨形态发生蛋白（BMP）-2，Msx 2和骨桥蛋白。在长链酰基辅酶A合成酶（ACSL）亚家族中，ACSL 3在HASMC中的表达占主导地位，PA强烈增加，EPA有效抑制ACSL 3表达。重要的是，PA诱导的成骨细胞分化至少部分是由ACSL 3活化介导的，因为酰基辅酶A合成酶（ACS）抑制剂或靶向ACSL 3的siRNA完全阻止了BMP-2和Msx 2的PA诱导。相反，腺病毒介导的ACSL 3过表达增强PA诱导的BMP-2和Msx 2表达。此外，EPA、ACSL 3 siRNA和ACS抑制剂可减弱PA诱导的钙沉积和caspase激活。值得注意的是，PA诱导NF-κB活化，NF-κB抑制剂阻止PA诱导的成骨细胞基因表达和钙沉积。免疫组化显示ACSL 3在人颈动脉非钙化和钙化动脉粥样硬化斑块中的VSMC和巨噬细胞中显著表达。这些结果确定ACSL 3和NF-κB是PA诱导的VSMC成骨细胞分化和钙沉积的介质，并表明EPA通过抑制PA引发的这种新分子途径来预防血管钙化。
Free fatty acids (FFAs), elevated in metabolic syndrome and diabetes, play a crucial role in the development of atherosclerotic cardiovascular disease, and eicosapentaenoic acid (EPA) counteracts many aspects of FFA-induced vascular pathology. Although vascular calcification is invariably associated with atherosclerosis, the mechanisms involved are not completely elucidated. In this study, we tested the hypothesis that EPA prevents the osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC) induced by palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma. PA increased and EPA abolished the expression of the genes for bone-related proteins, including bone morphogenetic protein (BMP)-2, Msx2 and osteopontin in human aortic smooth muscle cells (HASMC). Among the long-chain acyl-CoA synthetase (ACSL) subfamily, ACSL3 expression was predominant in HASMC, and PA robustly increased and EPA efficiently inhibited ACSL3 expression. Importantly, PA-induced osteoblastic differentiation was mediated, at least in part, by ACSL3 activation because acyl-CoA synthetase (ACS) inhibitor or siRNA targeted to ACSL3 completely prevented the PA induction of both BMP-2 and Msx2. Conversely, adenovirus-mediated ACSL3 overexpression enhanced PA-induced BMP-2 and Msx2 expression. In addition, EPA, ACSL3 siRNA and ACS inhibitor attenuated calcium deposition and caspase activation induced by PA. Notably, PA induced activation of NF-κB, and NF-κB inhibitor prevented PA-induction of osteoblastic gene expression and calcium deposition. Immunohistochemistry revealed the prominent expression of ACSL3 in VSMC and macrophages in human non-calcifying and calcifying atherosclerotic plaques from the carotid arteries. These results identify ACSL3 and NF-κB as mediators of PA-induced osteoblastic differentiation and calcium deposition in VSMC and suggest that EPA prevents vascular calcification by inhibiting such a new molecular pathway elicited by PA.
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影响因子：
--
作者：
BURGESS, NA;REYNOLDS, TM;SMITH, S
通讯作者：
SMITH, S
DOI：
10.1161/atvbaha.106.136853
发表时间：
2007-09-01
影响因子：
8.7
作者：
Itoh, Michiko;Suganami, Takayoshi;Ogawa, Yoshihiro
通讯作者：
Ogawa, Yoshihiro
影响因子：
3.7
作者：
Matsui H;Yokoyama T;Sekiguchi K;Iijima D;Sunaga H;Maniwa M;Ueno M;Iso T;Arai M;Kurabayashi M
通讯作者：
Kurabayashi M
影响因子：
9.8
作者：
Mugabo, Yves;Mukaneza, Yvette;Renier, Genevieve
通讯作者：
Renier, Genevieve
影响因子：
7.7
作者：
Fagot-Campagna, A;Balkau, B;Eschwège, E
通讯作者：
Eschwège, E