期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 7, 期 1, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.117.007405
关键词
atherosclerosis; IKK beta; nuclear factor-kappa B; vascular biology; vascular calcification
资金
- Japan Society for the Promotion of Science KAKENHI [25461497, 16H05297]
- Otsuka Pharmaceutical Co Ltd.
- Grants-in-Aid for Scientific Research [25461497, 16H05297] Funding Source: KAKEN
Background-Vascular calcification was previously considered as an advanced phase of atherosclerosis; however, recent studies have indicated that such calcification can appear in different situations. Nevertheless, there has been a lack of mechanistic insight to explain the difference. For example, the roles of nuclear factor-kappa B, a major regulator of inflammation, in vascular calcification are poorly explored, although its roles in atherosclerosis were well documented. Herein, we investigated the roles of nuclear factor-kappa B signaling in vascular calcification. Methods and Results-We produced mice with deletion of IKK beta, an essential kinase for nuclear factor-kappa B activation, in vascular smooth muscle cells (VSMCs; KO mice) and subjected them to the CaCl2-induced aorta injury model. Unexpectedly, KO mice showed more calcification of the aorta than their wild-type littermates, despite the former's suppressed nuclear factor-kappa B activity. Cultured VSMCs from the aorta of KO mice also showed significant calcification in vitro. In the molecular analysis, we found that Runt-related transcription factor 2, a transcriptional factor accelerating bone formation, was upregulated in cultured VSMCs from KO mice, and its regulator beta-catenin was more activated with suppressed ubiquitination in KO VSMCs. Furthermore, we examined VSMCs from mice in which kinase-active or kinase-dead IKK beta was over expressed in VSMCs. We found that kinase-independent function of IKK beta is involved in suppression of calcification via inactivation of b-catenin, which leads to suppression of Runt-related transcription factor 2 and osteoblast marker genes. Conclusions-IKK beta negatively regulates VSMC calcification through beta-catenin-Runt-related transcription factor 2 signaling, which revealed a novel function of IKK beta on vascular calcification.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据