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J Am Heart Assoc. 2018 Jan 4;7(1). pii: e007405. doi: 10.1161/JAHA.117.007405.

Deletion of IκB-Kinase β in Smooth Muscle Cells Induces Vascular Calcification Through β-Catenin-Runt-Related Transcription Factor 2 Signaling.

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Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan



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-κB, 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-κB signaling in vascular calcification.


We produced mice with deletion of IKKβ, an essential kinase for nuclear factor-κB 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-κB 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 β-catenin was more activated with suppressed ubiquitination in KO VSMCs. Furthermore, we examined VSMCs from mice in which kinase-active or kinase-dead IKKβ was overexpressed in VSMCs. We found that kinase-independent function of IKKβ is involved in suppression of calcification via inactivation of β-catenin, which leads to suppression of Runt-related transcription factor 2 and osteoblast marker genes.


IKKβ negatively regulates VSMC calcification through β-catenin-Runt-related transcription factor 2 signaling, which revealed a novel function of IKKβ on vascular calcification.


IKKβ; atherosclerosis; nuclear factor‐κB; vascular biology; vascular calcification

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