on November 11, 2004
Published online before print November 11, 2004, doi: 10.1161/01.ATV.0000150045.27127.37
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Submitted on January 21, 2004
Accepted on September 17, 2004
Role of ADAMTS-1 in Atherosclerosis. Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican
Ann-Cathrine Jönsson-Rylander ;
From the Department of Molecular Pharmacology (A.-C.J.-R., T.N., A.-K.A., B.R., P.B., E.H.-C, C.-H.L.-S.), Integrative Pharmacology (R.F.-D., M.B.), Molecular Science (A.T.), and Safety Assessment (A.W.), AstraZeneca R&D, Mölndal, Sweden; Arexis (J.-O.A., K.L.), Gothenburg, Sweden; and Apoteket AB (P.W.), Umeå, Sweden.
* To whom correspondence should be addressed. E-mail: chung-hyun.lee-sogaard{at}astrazeneca.com.
Objective--We investigated the potential role of ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type I) in atherogenesis.
Methods and Results--ADAMTS-1 is expressed at the highest levels in the aorta when compared with other human tissues examined. Immunolocalization studies in human aorta and coronary artery indicate that ADAMTS-1 expression is mainly seen at low levels in the medial layer, but upregulated in the intima when plaque is present. We found that ADAMTS-1 mRNA levels are significantly higher in proliferating/migrating cultured primary aortic vascular smooth muscle cells (VSMCs) compared with resting/confluent cells. Using the mouse carotid artery flow cessation model, we show that there are differences in vessel remodeling in ADAMTS-1 transgenic/apoE-deficient mice compared with apoE deficiency alone, particularly a significant increase in intimal hyperplasia. We show that ADAMTS-1 can cleave the large versican containing proteoglycan population purified from cultured human aortic VSMCs. Finally, using versican peptide substrates, we show data suggesting that ADAMTS-1 cleaves versican at multiple sites.
Conclusion--We hypothesize that ADAMTS-1 may promote atherogenesis by cleaving extracellular matrix proteins such as versican and promoting VSMC migration.
Key words: ADAMTS-1 • atherosclerosis • versican • neointima
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