| First Author | Al-Huseini I | Year | 2018 |
| Journal | J Am Heart Assoc | Volume | 7 |
| Issue | 1 | PubMed ID | 29301759 |
| Mgi Jnum | J:329851 | Mgi Id | MGI:6851064 |
| Doi | 10.1161/JAHA.117.007405 | Citation | Al-Huseini I, et al. (2018) Deletion of IkappaB-Kinase beta in Smooth Muscle Cells Induces Vascular Calcification Through beta-Catenin-Runt-Related Transcription Factor 2 Signaling. J Am Heart Assoc 7(1) |
| abstractText | 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-kappaB, 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-kappaB signaling in vascular calcification. METHODS AND RESULTS: We produced mice with deletion of IKKbeta, an essential kinase for nuclear factor-kappaB 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-kappaB 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 IKKbeta was overexpressed in VSMCs. We found that kinase-independent function of IKKbeta is involved in suppression of calcification via inactivation of beta-catenin, which leads to suppression of Runt-related transcription factor 2 and osteoblast marker genes. CONCLUSIONS: IKKbeta negatively regulates VSMC calcification through beta-catenin-Runt-related transcription factor 2 signaling, which revealed a novel function of IKKbeta on vascular calcification. |
