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(Circulation. 2003;107:2829.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Neutrophil Elastase in Human Atherosclerotic Plaques

Production by Macrophages

Clare M. Dollery, MRCP, PhD; Caroline A. Owen, FRCP, PhD; Galina K. Sukhova, PhD; Alexandra Krettek, PhD; Steven D. Shapiro, MD; Peter Libby, MD

From the Leducq Center for Cardiovascular Research (C.M.D., G.K.S., A.K., P.L.), Cardiovascular Division, and the Division of Pulmonary and Critical Care Medicine (C.A.O., S.D.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, EBRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Background— Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity.

Methods and Results— Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1ß, TNF-, or IFN- but released it when stimulated by CD40 ligand, a cytokine found in atheroma.

Conclusions— These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

Key Words: atherosclerosis • remodeling • arteries • vessels • inflammation

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