Effect of a coronary-heart-disease-associated variant of ADAMTS7 on endothelial cell angiogenesis

Xiangyuan Pu; Kenneth Chan; Wei Yang; Qingzhong Xiao; Li Zhang; Andrew D Moore; Chuanju Liu; Tom R Webb; Mark J Caulfield; Nilesh J Samani; Jianhua Zhu; Shu Ye

doi:10.1016/j.atherosclerosis.2020.01.015

Effect of a coronary-heart-disease-associated variant of ADAMTS7 on endothelial cell angiogenesis

Atherosclerosis. 2020 Mar:296:11-17. doi: 10.1016/j.atherosclerosis.2020.01.015. Epub 2020 Jan 21.

Authors

Xiangyuan Pu¹, Kenneth Chan², Wei Yang³, Qingzhong Xiao⁴, Li Zhang⁵, Andrew D Moore⁴, Chuanju Liu⁶, Tom R Webb⁷, Mark J Caulfield⁴, Nilesh J Samani⁷, Jianhua Zhu⁵, Shu Ye⁸

Affiliations

¹ First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; William Harvey Research Institute, Queen Mary University of London, London, UK.
² William Harvey Research Institute, Queen Mary University of London, London, UK; Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Shantou University Medical College, Shantou, China.
⁴ William Harvey Research Institute, Queen Mary University of London, London, UK.
⁵ First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ Musculoskeletal Research Center, New York University School of Medicine, New York, NY, USA.
⁷ Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
⁸ Shantou University Medical College, Shantou, China; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK. Electronic address: s_ye@stu.edu.cn.

PMID: 32005000
DOI: 10.1016/j.atherosclerosis.2020.01.015

Abstract

Background and aims: Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis.

Methods and results: ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody.

Conclusions: The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.

Keywords: ADAMTS7; Angiogenesis; Atherosclerosis; Endothelial cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAMTS7 Protein / biosynthesis
ADAMTS7 Protein / genetics
Amino Acid Substitution
Cell Movement
Culture Media, Conditioned / pharmacology
Endothelial Cells / physiology*
Gene Knockdown Techniques
Human Umbilical Vein Endothelial Cells
Humans
Neovascularization, Physiologic / genetics*
Plaque, Atherosclerotic / pathology
Polymorphism, Single Nucleotide*
Proteomics
RNA Interference
RNA, Small Interfering / genetics
Recombinant Proteins / metabolism
Thrombospondin 1 / immunology
Thrombospondin 1 / metabolism*

Substances

Culture Media, Conditioned
RNA, Small Interfering
Recombinant Proteins
Thrombospondin 1
ADAMTS7 Protein
ADAMTS7 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding