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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1354.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Low Levels of Nogo-B in Human Carotid Atherosclerotic Plaques Are Associated With an Atheromatous Phenotype, Restenosis, and Stenosis Severity

Juan A. Rodriguez-Feo; Willem E. Hellings; Bart A.N. Verhoeven; Frans L. Moll; Dominique P.V. de Kleijn; Jay Prendergast; Yuan Gao; Yolanda van der Graaf; George Tellides; William C. Sessa; Gerard Pasterkamp

From the Department of Cardiology, Experimental Cardiology Laboratory (J.A.R.-F., W.E.H., B.A.N.V., D.P.V.d.K., G.P.), University Medical Center, Utrecht, the Netherlands; the Interuniversity Cardiology Institute of the Netherlands (ICIN) (D.P.V.d.K., G.P.), Utrecht, the Netherlands; the Department of Vascular Surgery (W.E.H., B.A.N.V., F.L.M.), University Medical Center, Utrecht, the Netherlands; the Department of Pharmacology (J.P., Y.G., W.C.S.), Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Conn; the Julius Center for Health Sciences and Primary Care (Y.v.d.G.), Utrecht, The Netherlands; and the Department of Surgery (G.T.), Yale University School of Medicine, New Haven, Conn.

Correspondence to Gerard Pasterkamp, MD, PhD, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. E-mail gpasterk{at}umcutrecht.nl

Objective— Reticulon-4/Nogo (Nogo-B) protects mouse arteries from lumen loss by reducing smooth muscle cell (SMC) migration and intimal thickening. Our goal was to determine plaque and circulating levels of Nogo-B in atherosclerotic and control subjects. Therefore, we studied the relationships between local Nogo-B, plaque characteristics, and clinical data in patients undergoing carotid endarterectomy.

Methods and Results— Western blot analysis showed that endarterectomy specimens from the femoral (n=19) and carotid arteries (n=145) contained significantly less Nogo-B than nonatherosclerotic mammary arteries (n=8; P<0.003) and aortas (n=15; P=0.03). Immunohistochemistry revealed that in atherosclerotic lesions, Nogo-B was expressed by macrophage/foam cells, SMC rich, and neo-vascularized areas. Atheromatous plaques (>40% fat content) showed a significant reduction in Nogo-B expression (P=0.002). Nogo-B expression levels were significantly lower in patients with more than 90% of carotid stenosis (P=0.04) or restenotic lesions after prior carotid intervention (duplex; P=0.01). In contrast, plasmatic levels of Nogo-B (soluble Nogo-B) did not differ between atherosclerotic subjects (n=68) and risk-factor matched controls (n=63; P=0.5).

Conclusion— Our findings suggest that local reduction of Nogo-B in atherosclerotic tissue might contribute to plaque formation and/or instability triggering luminal narrowing. In contrast, plasma Nogo-B levels are not associated with clinically manifested atherosclerotic disease.

Nogo B protects arteries from lumen loss by reducing smooth muscle cell migration and intimal thickening. We report that low levels of Nogo B are associated with atheromatous plaques and stenotic lesions. Therefore, reduction of Nogo B in atherosclerotic tissue might contribute to plaque formation and/or instability triggering luminal narrowing.

Key Words: atherosclerosis • restenosis • vascular biology • Nogo-B

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