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J Bone Miner Res. 2017 May;32(5):927-938. doi: 10.1002/jbmr.3073. Epub 2017 Feb 23.

Nedd4 Deficiency in Vascular Smooth Muscle Promotes Vascular Calcification by Stabilizing pSmad1.

Author information

1
Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea.
2
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea.
3
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
4
Department of Dental Regenerative Technology, School of Dentistry, Seoul National University, Dental Research, Institute, Seoul, Korea.
5
Division of Vascular Surgery, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea.

Abstract

The nonosseous calcification process such as atherosclerosis is one of the major complications in several types of metabolic diseases. In a previous study, we uncovered that aberrant activity of transforming growth factor β (TGF-β) signaling pathway could contribute to the vascular smooth muscle cells' (VSMCs) calcification process. Also, we identified NEDD4 E3 ligase as a key suppressor of bone morphogenetic protein (BMP)/Smad pathway via a polyubiquitination-dependent selective degradation of C-terminal phosphorylated Smad1 (pSmad1) activated by TGF-β. Here, we further validated and confirmed the role of Nedd4 in in vivo vascular calcification progression. First, Nedd4 deletion in SM22α-positive mouse tissues (Nedd4fl/fl ;SM22α-Cre) showed deformed aortic structures with disarranged elastin fibers at 24 weeks after birth. Second, vitamin D-induced aorta vascular calcification rate in Nedd4fl/fl ;SM22α-Cre mice was significantly higher than their wild-type littermates. Nedd4fl/fl ;SM22α-Cre mice showed a development of vascular calcification even at very low-level injection of vitamin D, but this was not exhibited in wild-type littermates. Third, we confirmed that TGF-β1-induced pSmad1 levels were elevated in Nedd4-deficient primary VSMCs isolated from Nedd4fl/fl ;SM22α-Cre mice. Fourth, we further found that Nedd4fl/fl ;SM22α-Cre mVSMCs gained mesenchymal cell properties toward osteoblast-like differentiation by a stable isotope labeling in cell culture (SILAC)-based proteomics analysis. Finally, epigenetic analysis revealed that methylation levels of human NEDD4 gene promoter were significantly increased in atherosclerosis patients. Collectively, abnormal expression or dysfunction of Nedd4 E3 ligase could be involved in vascular calcification of VSMCs by activating bone-forming signals during atherosclerosis progression.

KEYWORDS:

NEDD4; OSTEOBLAST DIFFERENTIATION; SMAD1; VASCULAR CALCIFICATION; VSMCS

PMID:
28029182
DOI:
10.1002/jbmr.3073
[Indexed for MEDLINE]
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