연구논문

세부과제번호 2014M3A9D5A01073598 단계 2단계 1차년도
세부과제명 IMPC 대사질환 표현형 마우스 오믹스 분석기반 구축 및 정보개발 공동 유/무 N
SCI여부 Y 게재년월 2016-12
논문제목 Nedd4 Deficiency in Vascular Smooth Muscle Promotes Vascular Calcification by Stabilizing pSmad1.
총저자명 Ji-Hyun LeeSeon-Ae JeonByung-Gyu KimMichiko TakedaJae-Jin ChoDong-Ik KimHiroshi KawabeJe-Yoel Cho
학술지명 J. Bone Miner. Res. 게재권(호) 32(5)
저널구분 - 페이지수 927-938
참여연구원 - 연구책임자 조제열
과제기여도 30 PMID 28029182
사사기관수 - IF (년도) 6.284
제1저자 Ji-Hyun Lee 교신저자 Je-Yoel Cho
공동저자 -
초록
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 (Nedd4(fl/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 Nedd4(fl/fl) ;SM22α-Cre mice was significantly higher than their wild-type littermates. Nedd4(fl/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 Nedd4(fl/fl) ;SM22α-Cre mice. Fourth, we further found that Nedd4(fl/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. © 2016 American Society for Bone and Mineral Research.
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