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Cartilage Oligomeric Matrix Protein Inhibits Vascular Smooth Muscle Calcification by Interacting With Bone Morphogenetic Protein-2.

Du, Yaoyao; Wang, Yue; Wang, Li; Liu, Bo; Tian, Qingyun; Liu, Chuan-Ju; Zhang, Tao; Xu, Qingbo; Zhu, Yi and Oldberg, Åke LU , et al. (2011) In Circulation research 108. p.79-917
Abstract
Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown. Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl(2) to the abdominal aorta. COMP protein level was markedly reduced in... (More)
Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown. Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl(2) to the abdominal aorta. COMP protein level was markedly reduced in both calcified VSMCs and arteries. COMP deficiency remarkably exacerbated VSMC calcification, whereas ectopic expression of COMP greatly reduced calcification. Furthermore, COMP knockdown facilitated osteogenic markers expression by VSMCs even in the absence of calcifying media. By contrast, COMP overexpression significantly inhibited high phosphate- or high calcium-induced VSMC osteochondrogenic transition. Induction of osteogenic marker expression by COMP silencing was reversed by a soluble form of bone morphogenetic protein (BMP)-2 receptor IA, which suggests a BMP-2-dependent mechanism. Our data revealed that COMP bound directly to BMP-2 through the C terminus, inhibited BMP-2 receptor binding, and blocked BMP-2 osteogenic signaling, indicating COMP inhibits osteochondrogenic transition of VSMCs at least partially through inhibiting BMP-2. Conclusions: Our data strongly suggest that COMP is a novel inhibitor of vascular calcification. The imbalance between the effects of COMP and BMP-2 may provide new insights into the pathophysiology of vascular calcification. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Circulation research
volume
108
pages
79 - 917
publisher
American Heart Association
external identifiers
  • WOS:000289510800006
  • PMID:21350216
  • Scopus:79954692715
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.110.234328
language
English
LU publication?
yes
id
d9d7a82b-dba2-4be9-9b95-60a2a7cba3da (old id 1831343)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21350216?dopt=Abstract
date added to LUP
2011-03-01 18:03:44
date last changed
2016-12-04 04:41:36
@misc{d9d7a82b-dba2-4be9-9b95-60a2a7cba3da,
  abstract     = {Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown. Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl(2) to the abdominal aorta. COMP protein level was markedly reduced in both calcified VSMCs and arteries. COMP deficiency remarkably exacerbated VSMC calcification, whereas ectopic expression of COMP greatly reduced calcification. Furthermore, COMP knockdown facilitated osteogenic markers expression by VSMCs even in the absence of calcifying media. By contrast, COMP overexpression significantly inhibited high phosphate- or high calcium-induced VSMC osteochondrogenic transition. Induction of osteogenic marker expression by COMP silencing was reversed by a soluble form of bone morphogenetic protein (BMP)-2 receptor IA, which suggests a BMP-2-dependent mechanism. Our data revealed that COMP bound directly to BMP-2 through the C terminus, inhibited BMP-2 receptor binding, and blocked BMP-2 osteogenic signaling, indicating COMP inhibits osteochondrogenic transition of VSMCs at least partially through inhibiting BMP-2. Conclusions: Our data strongly suggest that COMP is a novel inhibitor of vascular calcification. The imbalance between the effects of COMP and BMP-2 may provide new insights into the pathophysiology of vascular calcification.},
  author       = {Du, Yaoyao and Wang, Yue and Wang, Li and Liu, Bo and Tian, Qingyun and Liu, Chuan-Ju and Zhang, Tao and Xu, Qingbo and Zhu, Yi and Oldberg, Åke and Qi, Yongfen and Tang, Chaochu and Kong, Wei and Wang, Xiangdong},
  issn         = {1524-4571},
  language     = {eng},
  pages        = {79--917},
  publisher    = {ARRAY(0x8adc168)},
  series       = {Circulation research},
  title        = {Cartilage Oligomeric Matrix Protein Inhibits Vascular Smooth Muscle Calcification by Interacting With Bone Morphogenetic Protein-2.},
  url          = {http://dx.doi.org/10.1161/CIRCRESAHA.110.234328},
  volume       = {108},
  year         = {2011},
}