ADAM33 expression in atherosclerotic lesions and relationship of ADAM33 gene variation with atherosclerosis

Holloway, John W.; Laxton, Ross C.; Rose-Zerilli, Matthew J.; Holloway, Judith A.; Andrews, A. Lynn; Riaz, Zeshan; Wilson, Susan J.; Simpson, Iain A.; Ye, Shu

doi:10.1016/j.atherosclerosis.2010.02.023

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Volume 211, Issue 1 , Pages 224-230, July 2010

ADAM33 expression in atherosclerotic lesions and relationship of ADAM33 gene variation with atherosclerosis

John W. Holloway
- Human Genetics, School of Medicine, University of Southampton, Southampton, UK
- Infection, Inflammation & Immunity, School of Medicine, University of Southampton, Southampton, UK
Ross C. Laxton
- Human Genetics, School of Medicine, University of Southampton, Southampton, UK
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Matthew J. Rose-Zerilli
- Human Genetics, School of Medicine, University of Southampton, Southampton, UK
- Infection, Inflammation & Immunity, School of Medicine, University of Southampton, Southampton, UK
Judith A. Holloway
- Infection, Inflammation & Immunity, School of Medicine, University of Southampton, Southampton, UK
A. Lynn Andrews
- Infection, Inflammation & Immunity, School of Medicine, University of Southampton, Southampton, UK
Zeshan Riaz
- Human Genetics, School of Medicine, University of Southampton, Southampton, UK
Susan J. Wilson
- Histochemistry Research Unit, School of Medicine, University of Southampton, Southampton, UK
Iain A. Simpson
- Cardiothoracic Unit, Southampton General Hospital, Southampton, UK
Shu Ye
- Human Genetics, School of Medicine, University of Southampton, Southampton, UK
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Corresponding author at: Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. Tel.: +44 207 882 3425; fax: +44 207 882 3408.

Received 5 August 2009; received in revised form 10 February 2010; accepted 17 February 2010. published online 15 March 2010.

Abstract

A-disintegrin-and-metalloproteinase-domains (ADAMs) are membrane-anchored glycoproteins involved in cell adhesion, cell migration and proteolysis. ADAM15 has been implicated in atherosclerosis, with an effect on vascular smooth muscle cell migration. We investigated whether ADAM33, which is evolutionally closely related to ADAM15, was expressed in atheromas and whether it had an effect on vascular smooth muscle migration. We also tested whether ADAM33 gene variation had an influence on the extent of atherosclerosis in patients with coronary artery disease. Immunohistochemical analyses showed that ADAM33 was expressed in smooth muscle cells in the arterial wall and that the expression was increased in smooth muscle cells in atheromas. ADAM33 immunostaining on inflammatory cells in atheromas was also observed. Primary vascular smooth muscle cells in culture were also found to express ADAM33. Boyden chamber assays showed that a neutralising antibody against ADAM33 increased the ability of arterial smooth muscle cells to migrate through a reconstituted basement membrane, suggesting that ADAM33 has an inhibitory effect on vascular smooth muscle migration. Moreover, we detected an association between ADAM33 genotype and the extent of atherosclerosis in a large cohort of coronary artery disease patients. These findings suggest that ADAM33 is implicated in the pathogenesis of atherosclerosis.

Keywords: ADAM33, Smooth muscle cells, Atherosclerosis, Genetic, Polymorphism