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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.

Author information

1
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan nashida@kuhp.kyoto-u.ac.jp.

Abstract

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-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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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

KEYWORDS:

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

PMID:
29301759
PMCID:
PMC5778968
DOI:
10.1161/JAHA.117.007405
[Indexed for MEDLINE]
Free PMC Article

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