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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1844.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Macrophages and Platelets Are the Major Source of Protease Nexin-1 in Human Atherosclerotic Plaque

Silvana Mansilla; Yacine Boulaftali; Laurence Venisse; Véronique Arocas; Olivier Meilhac; Jean-Baptiste Michel; Martine Jandrot-Perrus; Marie-Christine Bouton

From INSERM, U698, Paris, -75877 France (S.M., Y.A., L.V., V.A., O.M., J.B.M., M.J.P., M.C.B.); and Univ Paris 7, UFR Médicale, Paris, F-75018 (J.B.M.); AP-HP, Hôpital Bichat, Paris, F-75877, France (MJP).

Correspondence to Dr Martine Jandrot-Perrus, Unité INSERM U698, CHU Xavier Bichat, 46 rue Henri Huchard 75877 Paris Cedex 18, France. E-mail martine.jandrot-perrus{at}inserm.fr

Objective— Protease nexin-1 (PN-1), a serpin constitutively expressed by vascular smooth muscle cells and endothelial cells, inhibits thrombin, plasminogen activators, and plasmin and can thus be expected to play a role in vascular biology. The present study addressed the question of PN-1 expression in human atherothrombosis.

Methods and Results— Immunohistochemistry and biochemical studies confirmed that PN-1 was expressed at a moderate level in the medial layer of normal human arteries and showed that PN-1 expression was increased in atherothrombotic lesions. In early noncomplicated plaques, PN-1 was associated with infiltrating mononuclear cells. A strong PN-1 signal was observed in advanced lesions, principally in intraplaque hemorrhage-related structures. Monocytes/macrophages and platelets were identified as the main sources of PN-1 within atherothrombotic material. Isolated human monocytes and platelets both expressed high levels of active PN-1, and monocyte PN-1 expression was upregulated, at both messenger and protein levels, in response to stimulation by lipopolysaccharides. In contrast, PN-1 expression was downregulated during their differentiation into macrophages which were shown to produce degraded forms of PN-1.

Conclusions— Platelets and monocytes/macrophages are a major source of PN-1 in human atherothrombotic plaques. PN-1 could thus represent a new actor in the evolution of atherosclerotic lesions.

Protease nexin-1 expression was analyzed in atherosclerotic carotid arteries. This serpin was highly expressed in the cap and in the necrotic core present in advanced lesions. Monocytes/macrophages and platelets are its main sources within the atherothrombotic lesion. Protease nexin-1 may thus have an impact in the development of atherosclerosis.

Key Words: protease nexin-1 • atherosclerosis • inflammatory cells • thrombin

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