miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_345D721A4C97
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).
Journal
Arteriosclerosis, thrombosis, and vascular biology
Author(s)
Badi I., Mancinelli L., Polizzotto A., Ferri D., Zeni F., Burba I., Milano G., Brambilla F., Saccu C., Bianchi M.E., Pompilio G., Capogrossi M.C., Raucci A.
ISSN
1524-4636 (Electronic)
ISSN-L
1079-5642
Publication state
Published
Issued date
09/2018
Peer-reviewed
Oui
Volume
38
Number
9
Pages
2079-2090
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a <sup>+/+</sup> and Mir34a <sup>-/-</sup> mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a <sup>-/-</sup> SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a <sup>+/+</sup> cells. Furthermore, unlike in Mir34a <sup>+/+</sup> SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a <sup>-/-</sup> SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.
Keywords
Adult, Aging/pathology, Animals, Aorta/metabolism, Cell Proliferation, Cells, Cultured, Cellular Senescence/physiology, Core Binding Factor Alpha 1 Subunit/metabolism, Down-Regulation, Humans, Male, Mice, Mice, Knockout, MicroRNAs/metabolism, Muscle, Smooth, Vascular/cytology, Muscle, Smooth, Vascular/metabolism, Myocytes, Smooth Muscle/metabolism, Proto-Oncogene Proteins/metabolism, Receptor Protein-Tyrosine Kinases/metabolism, SOX9 Transcription Factor/metabolism, Sirtuin 1/metabolism, Up-Regulation, Vascular Calcification, Young Adult, aging, humans, mice, senescence, vascular calcification
Pubmed
Web of science
Open Access
Yes
Create date
31/07/2018 11:48
Last modification date
20/08/2019 13:21
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