![]() ![]() ![]() 18 This peroxidase-positive subpopulation of monocytes also contains NE and cathepsin G in the subcellular peroxidase granules. Subpopulations of mononuclear phagocytes, “proinflammatory” (P) monocytes, express enzymes such as myeloperoxidase, traditionally associated with granulocytes. Although less well recognized, humans deficient in α-1-PI can also have fibromuscular dysplasia in the carotid and intracranial arteries, indicating an additional role for this enzyme in arterial biology. 15,16 Inherited deficiency of α1-proteinase inhibitor (α-1-PI), the principle extracellular inhibitor of NE, increases risk of severe early-onset emphysema. Cigarette smoking, which augments NE release in the lung, also contributes to atherothrombosis. NE catastrophically promotes lung diseases such as emphysema. 12 NE also has a proatherogenic role in lipid metabolism by virtue of its ability to modify apolipoproteins resulting in HDL destruction, enhanced LDL uptake, and foam cell formation. It modulates the activation of nonmyeloid cells such as platelets, promoting aggregation, and augments both thrombosis and fibrinolysis by cleavage of clotting factors and their inhibitors. 6 NE has other actions of potential importance in the vasculature. 8–10 In addition to matrix breakdown, NE also regulates the activity of cytokines such as IL-β, TNF-α, and IL-8 11 and cleaves the TNF-α 75-kDa receptor and T-cell surface proteins CD2, CD4, and CD8. 6 NE swings the proteolytic balance in favor of matrix breakdown by activating MMP-2, MMP-3, and MMP-9 and by inactivating their inhibitor, TIMP-1. 7 NE degrades not only elastin but also fibronectin, laminin, collagen III, IV, and VI, and proteoglycans. 6 It is predominantly present in neutrophils and has an important role in defense against infection. ![]() Myeloid precursor cells produce and activate NE in the bone marrow, and neutrophils store this 218–amino acid glycoprotein in lysosomal granules. 5 This finding suggested to us that neutrophil elastase (NE) might also play a broader role than its name implies. 2–4 We recently demonstrated that nonmyeloid cells found in atheroma express MMP-8, a collagenase previously associated with neutrophils. 1 A broad spectrum of elastolytic enzymes exists, including metalloelastases and cysteine proteases such as the cathepsins. Proteolysis and elastolysis contribute to the development of both occlusive and aneurysmal arterial diseases. Monocytes produced NE constitutively, with little regulation by cytokines IL-1β, TNF-α, or IFN-γ but released it when stimulated by CD40 ligand, a cytokine found in atheroma.Ĭonclusions- 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. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Methods and Results- Fibrous and atheromatous plaques but not normal arteries contained NE. 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. 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. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. 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. Customer Service and Ordering Informationīackground- Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). ![]()
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