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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2359-2368.)
© 1997 American Heart Association, Inc.

Articles

Calreticulin, a Potential Vascular Regulatory Protein, Reduces Intimal Hyperplasia After Arterial Injury

E. Dai; M. Stewart; B. Ritchie; N. Mesaeli; S. Raha; D. Kolodziejczyk; M. Lundstrom Hobman; L. Y. Liu; W. Etches; N. Nation; M. Michalak; ; A. Lucas

From the Cardiovascular Disease Research Group and the Department of Medicine, University of Alberta, and Vascular Biology Group, Robarts Research Institute and Department of Medicine, University of Western Ontario (E.D., D.K., M.L.H., L.Y.L., A.L.); the MRC Group in Molecular Biology of Membranes and Department of Biochemistry, University of Alberta (N.M., M.M.); the Department of Laboratory Animal Medicine, University of Alberta (N.N.); the Division of Hematology and Department of Medicine, University of Alberta (B.R., S.R.); and the Department of Pathology, University of Alberta (M.S., W.E.).

Correspondence to Alexandra Lucas, MD, Vascular Biology Group, The John P. Robarts Research Institute, PO Box 5015, 100 Perth Dr, London, Ontario N6A 5K8. E-mail arl{at}rri.on.ca

Abstract Both thrombotic and inflammatory responses to arterial injury have been implicated in atherosclerotic plaque growth. Calreticulin is a ubiquitous calcium-binding protein with antithrombotic activity and, in addition, is associated with leukocyte activation. We are investigating calreticulin as a potential vascular regulatory protein. The development of intimal hyperplasia was studied at sites of balloon injury in iliofemoral arteries from 91 rats. Calreticulin was infused directly into the artery immediately before balloon injury, and plaque growth was then assessed at 4 weeks' follow-up. Parallel studies of the effects of each calreticulin domain as well as a related calcium-binding protein, calsequestrin, were examined. The effects of calreticulin on platelet activation, clot formation, and mononuclear cell migration were also studied. When infused before balloon injury in rat iliofemoral arteries, calreticulin, or its high-capacity Ca²⁺-binding C domain, significantly reduces plaque development, whereas calsequestrin, a related calcium-binding protein that lacks the multifunctional nature of calreticulin, does not decrease plaque area (saline: 0.037±0.007 mm², calsequestrin: 0.042±0.021 mm², calreticulin: 0.003±0.002 mm², n=46, P<.04). The N domain and more specifically the P domain, a low-capacity, high-affinity calcium-binding domain in calreticulin, do not reduce intimal hyperplasia (N+P domain: 0.038±0.012 mm², C domain: 0.003±0.002 mm², n=45 rats, P<.0001). Calreticulin reduces macrophage and T cell staining in the arterial wall after injury but has no direct effect on monocyte migration in vitro (percent medial area staining positive for macrophage 24 hours after injury (N+P: 4.06±1.42, calreticulin: 0.273±0.02; n=26, P<.009). Calreticulin does, however, reduce platelet-dependent whole blood clotting time, in vitro (baseline: 78.23±2.04 seconds, calreticulin: 113.5±1.95 seconds; n=5, P<.002). We conclude that calreticulin significantly reduces intimal hyperplasia after arterial injury, potentially acting as a vascular regulatory protein.

Key Words: atherosclerosis • thrombosis • calreticulin • monocytes

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