Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases.
Wnt signaling contributes to vascular calcification by induction of matrix metalloproteinases.
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DOI：
10.1186/s12872-016-0362-8
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发表时间：
2016-09-30
影响因子：
2.1
通讯作者：
Querfeld U
中科院分区：
文献类型：
--
作者：
Freise C;Kretzschmar N;Querfeld U
血管钙化，如动脉硬化，其特征是中膜钙化，是主要的并发症，例如在慢性肾脏疾病(CKD)患者中。动脉硬化发展过程中的一个重要步骤是类似成骨的血管平滑肌细胞(VSMC)的转分化/钙化。在临床前研究中发现基质金属蛋白酶-2和−-9促进了这些血管平滑肌细胞的钙化，它们的抑制对预防动脉硬化具有治疗价值。为了了解MMPs的潜在调控机制，我们在此研究了MMPs介导的VSMC钙化是否涉及Wnt通路的信号改变，这是已知的影响成骨的信号通路。我们使用了一种血管钙化的体外实验模型。高钙、高磷可诱导小鼠VSMC转分化/钙化。钙化程度通过测定钙和碱性磷酸酶来评估。通过荧光标记底物的转换来评估明胶酶MMP2和MMP9的激活/活性。用报告基因分析Wnt通路的激活情况。除促钙化培养条件外，特定激动剂(在正常培养条件下)激活Wnt信号也可刺激VSMC钙化并促进明胶酶−-2和−9的表达和分泌。反之，重组MMP2和MMP9在72h诱导Wnt信号的延迟激活，但在24-48h没有直接作用，这些作用可被MMPs或Wnt信号的药物抑制所阻断。我们的研究表明，CKD的促钙化环境诱导VSMC中的Wnt信号转导，进而促进MMPs的诱导，从而促进动脉硬化的发展。因此，除抑制基质金属蛋白酶外，抑制VSMC中的Wnt信号可能是预防血管钙化的一个治疗靶点。本文的在线版本(doi：10.1186/s12872-0160362-8)包含补充材料，授权用户可以使用。
Vascular calcifications such as arteriosclerosis, which is characterized by a calcificiation of the tunica media, represent major comorbidities e.g. in patients with chronic kidney disease (CKD). An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMC) resembling osteogenesis. The matrix metalloproteinases (MMP)-2 and −9 were shown to promote these VSMC calcifications and their inhibition is of therapeutic value to prevent arteriosclerosis in preclinical studies. Aiming for an understanding of the underlying regulatory mechanisms of MMPs we here investigated, if the MMP-mediated VSMC calcification involves altered signaling of the Wnt pathway, which is known to impact osteogenesis. We used an experimental in vitro model of vascular calcification. Transdifferentiation/calcification of murine VSMC was induced by elevated calcium and phosphorus levels. Calcification was assessed by calcium and alkaline phosphatase measurements. Activation/activity of the gelatinases MMP-2 and MMP-9 was assessed by conversion of fluorescence-labelled substrates. Activation of the Wnt pathway was analysed by a reporter gene assay. Besides pro-calcifying culture conditions, also activation of Wnt signaling by a specific agonist (under normal culture conditions) stimulated VSMC-calcification accompanied by enhanced expression and secretion of the gelatinases MMP-2 and −9. Vice versa, recombinant MMP-2 and −9 induced a time-delayed activation of Wnt signaling after 72 h in VSMC but showed no direct effects after 24–48 h. These effects were blocked by pharmacological inhibition of MMPs or of Wnt signaling. Our study suggests that the pro-calcifying environment in CKD induces Wnt signaling in VSMC which in turn contributes to the induction of MMPs which then foster the development of arteriosclerosis. Thus, besides MMP inhibition, the inhibition of Wnt signaling in VSMC might represent a therapeutic target for the prevention of vascular calcifications. The online version of this article (doi:10.1186/s12872-016-0362-8) contains supplementary material, which is available to authorized users.
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影响因子：
40.5
作者：
Thompson, Bithika;Towler, Dwight A.
通讯作者：
Towler, Dwight A.
DOI：
10.1152/ajprenal.00684.2011
发表时间：
2012-10-01
影响因子：
4.2
作者：
Martinez-Moreno, Julio M.;Munoz-Castaneda, Juan R.;Almaden, Yolanda
通讯作者：
Almaden, Yolanda
影响因子：
13.5
作者：
Benyon, RC;Hovell, CJ;Arthur, MJP
通讯作者：
Arthur, MJP
影响因子：
20.1
作者：
Shanahan CM;Crouthamel MH;Kapustin A;Giachelli CM
通讯作者：
Giachelli CM
影响因子：
32.4
作者：
Wu, Beibei;Crampton, Steve P.;Hughes, Christopher C. W.
通讯作者：
Hughes, Christopher C. W.