Published online before print December 29, 2003, doi: 10.1161/01.CIR.0000109140.51366.72
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(Circulation. 2004;109:393-398.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling
From the Experimental Cardiology Laboratory, HLCU, University Medical Center, Utrecht, the Netherlands (S.C.G.H., K.v.K., A.H.S., A.V., C.F.S., B.J.v.M., G.P., D.P.V.d.K.); Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (S.C.G.H., A.H.S., A.V., C.F.S., D.P.V.d.K.); TNO-PG, Leiden, the Netherlands (M.R.d.V., P.H.A.Q.); and the Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (P.H.A.Q.).
Correspondence to D.P.V. de Kleijn, PhD, Experimental Cardiology Laboratory, University Medical Center, Room G02–523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail d.dekleijn{at}hli.azu.nl
Received March 25, 2003; de novo received July 15, 2003; revision received September 16, 2003; accepted September 16, 2003.
Background— Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling is characterized by matrix turnover and a structural change in arterial circumference and is associated with a vulnerable plaque phenotype. Since Tlr4 ligands are expressed during matrix turnover, we hypothesized that Tlr4 is involved in arterial remodeling.
Methods and Results— In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. With the use of the same model in wild-type mice, neointima formation and outward remodeling occurred. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. Carotid artery ligation in wild-type mice resulted in outward remodeling without neointima formation in the contralateral artery. This was associated with an increase in Tlr4 expression and EDA and Hsp60 mRNA levels. In contrast, outward remodeling was not observed after carotid ligation in Tlr4-deficient mice.
Conclusions— These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.
Key Words: remodeling • arteries • plaque • atherosclerosis • proteins
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