Deletion of I kappa B- Kinase beta in Smooth Muscle Cells Induces Vascular Calcification Through beta-Catenin-Runt-Related Transcription Factor 2 Signaling

作者：Al Huseini Isehaq; Ashida Noboru; Kimura Takeshi

来源：Journal of the American Heart Association, 2018, 7(1): e007405.

DOI：10.1161/JAHA.117.007405

<jats:sec xml:lang="en">
<jats:title>Background</jats:title>
<jats:p xml:lang="en">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.</jats:p>
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<jats:sec xml:lang="en">
<jats:title>Methods and Results</jats:title>
<jats:p xml:lang="en">
We produced mice with deletion of
<jats:styled-content style="fixed-case">IKK</jats:styled-content>
β, an essential kinase for nuclear factor‐κB activation, in vascular smooth muscle cells (VSMCs; KO mice) and subjected them to the CaCl
<jats:sub>2</jats:sub>
‐induced aorta injury model. Unexpectedly,
<jats:styled-content style="fixed-case">KO</jats:styled-content>
mice showed more calcification of the aorta than their wild‐type littermates, despite the former's suppressed nuclear factor‐κB activity. Cultured
<jats:styled-content style="fixed-case">VSMC</jats:styled-content>
s from the aorta of
<jats:styled-content style="fixed-case">KO</jats:styled-content>
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
<jats:styled-content style="fixed-case">VSMC</jats:styled-content>
s from
<jats:styled-content style="fixed-case">KO</jats:styled-content>
mice, and its regulator β‐catenin was more activated with suppressed ubiquitination in
<jats:styled-content style="fixed-case">KO VSMC</jats:styled-content>
s. Furthermore, we examined
<jats:styled-content style="fixed-case">VSMC</jats:styled-content>
s from mice in which kinase‐active or kinase‐dead
<jats:styled-content style="fixed-case">IKK</jats:styled-content>
β was overexpressed in
<jats:styled-content style="fixed-case">VSMC</jats:styled-content>
s. We found that kinase‐independent function of
<jats:styled-content style="fixed-case">IKK</jats:styled-content>
β 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.
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</jats:sec>
<jats:sec xml:lang="en">
<jats:title>Conclusions</jats:title>
<jats:p xml:lang="en">
<jats:styled-content style="fixed-case">IKK</jats:styled-content>
β negatively regulates
<jats:styled-content style="fixed-case">VSMC</jats:styled-content>
calcification through β‐catenin–Runt‐related transcription factor 2 signaling, which revealed a novel function of
<jats:styled-content style="fixed-case">IKK</jats:styled-content>
β on vascular calcification.
</jats:p>
</jats:sec>

• 出版日期2018-1