serval:BIB_345D721A4C97
miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).
10.1161/ATVBAHA.118.311298
000442507900013
30026277
Badi
I.
author
Mancinelli
L.
author
Polizzotto
A.
author
Ferri
D.
author
Zeni
F.
author
Burba
I.
author
Milano
G.
author
Brambilla
F.
author
Saccu
C.
author
Bianchi
M.E.
author
Pompilio
G.
author
Capogrossi
M.C.
author
Raucci
A.
author
article
2018-09
Arteriosclerosis, thrombosis, and vascular biology
1524-4636
1079-5642
journal
38
9
2079-2090
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
University of Lausanne
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