N -Acetyl-Cysteine Decreases the Matrix-Degrading Capacity of Macrophage-Derived Foam Cells

Abstract

Background-Atherosclerotic plaque destabilization triggers clinical cardiovascular disease and thus represents an attractive therapeutic target. Weakening of tissue through the action of matrix-degrading enzymes, called matrix metalloproteinases (MMPs), released by resident macrophages was previously implicated in unstable vascular syndromes. Methods and Results-We used a hypercholesterolemic rabbit model of atherosclerosis to investigate the gelatinolytic activity associated with macrophage-derived foam cells (FCs). Gelatinolytic activity and expression of MMP-9 but not of MMP-2 cosegregated with macrophage FCs in aortic lesions. Macrophage-derived gelatinases were further investigated in vitro. MMP-9 was identified as the main macrophage-derived gelatinase in cells isolated from aortic lesions and from granuloma induced in the same rabbits to increase cell yield. Importantly, detection of activated MMP-9 in the FC culture medium supports the notion that these cells can independently initiate processing of secreted MMP zymogens to active enzymes. We further examined whether FC gelatinolytic activity is dependent on the presence of reactive oxygen species (ROS). We found that treatment (1 to 5 days) with 1 to 10 mmol/L N-acetyl-L-cysteine (NAC), an ROS scavenger, decreased not only gelatinolytic activity but also gelatinase expression by FCs. Similarly, NAC treatment of explanted lesions abolished in situ gelatinolytic activity and MMP-9 expression. Conclusions-Macrophage FCs are an abundant source of gelatinolytic activity that can be inhibited in vitro and in situ by NAC. This newly described action of antioxidant therapy might prove useful to inhibit matrix degradation and to improve vascular stability. (Circulation. 1998;97:2445-2453.)

Smoking, Metalloproteinases, and Vascular Disease

“…3 Cigarette smoke-induced inflammation and oxidative stress have the potential to induce and inhibit matrix metalloproteinase activity at multiple levels. Reactive oxygen species 92 and decreased nitric oxide activity 93 induce matrix metalloproteinase transcription. Cigarette smoke may increase matrix metalloproteinase expression via activation of inflammatory transcription factors.…”

“…101 Reactive oxygen species activate latent proforms of matrix metalloproteinases, 102 and antioxidant species decrease matrix metalloproteinase expression and activation. 92 Nitric oxide inhibits matrix metalloproteinase activation. 103 IL-1␤ decreases tissue inhibitor of metalloproteinase expression.…”

C242T CYBA Polymorphism of the NADPH Oxidase Is Associated With Reduced Respiratory Burst in Human Neutrophils

“…36 Furthermore, atherosclerotic plaque rupture in areas of the shoulder region where NADPH oxidase-containing monocytes/macrophages and neutrophils are recruited is known to be promoted by superoxide. [37][38][39] In addition, neutrophils from patients with acute myocardial infarction and peripheral obstructive atherosclerotic disease produce more superoxide anion compared with neutrophils of healthy controls. 40,41 The potential for identifying subjects with genetically altered susceptibilities to oxidative stress and confirmation of the presence of the C242T CYBA polymorphism thus could provide a novel genetic marker for cardiovascular risk assessment.…”

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

“…This protease family includes 72-kDa gelatinase A (MMP-2) and 92-kDa gelatinase B (MMP-9) that degrade type IV collagen and gelatin. Shear stress, vascular injury, inflammation, and oxidative stress have been shown to regulate MMP expression and activity via the production of ROS [21][22][23][24]. However, it remains unclear whether the ox-PAPC affects vascular endothelial MMP expression and activities.…”