(Circulation. 1999;99:2496-2498.)
© 1999 American Heart Association, Inc.
Editorial |
Increased Plasminogen Activator Inhibitor-1 and Vasculopathy
A Reconcilable Paradox
From the Department of Medicine, The University of Vermont College of Medicine, Burlington,Vt.
Correspondence to Dr Burton E. Sobel, Department of Medicine, The University of Vermont College of Medicine, Colchester Research Facility, 55A S Park Dr, Colchester, VT 05446. E-mail burton.sobel@vtmednet.org
Key Words: Editorials • plasminogen activators • coronary disease • diabetes mellitus
A Paradox
Altered activities of plasminogen activator (PA) and plasminogen activator inhibitor type-1 (PAI-1) in vessels are associated with atherosclerosis.1 2 3 4 5 However, their impacts on the inferred pathogenetic mechanisms seem contradictory. Proteolysis mediated by PAs contributes to vascular smooth muscle migration, neointimalization, and activation of matrix metalloproteases (MMPs) that precipitate plaque rupture.6 7 8 Conversely, PAI-1 is increased in blood and vessel walls with type 2 diabetes mellitus, yet the incidence of acute coronary syndromes (ACS) precipitated by plaque rupture is extraordinarily high.9 10 11 12
Atherogenesis entails13 the following steps: activation of monocytes/macrophages14 by oxidized LDL15 and expression of monocyte chemotactic activating factors such as leukocyte CXCR-2 and its homologs and ligands16 ; their migration into the neointima and elaboration of MMPs7 ; consequent fragmentation of the internal elastic lamina; accumulation of lipid; migration and subsequent proliferation of vascular smooth muscle cells (VSMCs)15 17 18 ; and proliferation of VSMCs that form largely cellular plaques that can obstruct flow. Until recently, such lesions were thought to account not only for effort-induced clinically stable angina pectoris but also for ACS including unstable angina, Q- and non–Q-wave myocardial infarction (MI), and sudden cardiac death.
Falk19 and Davies et al20 identified an
important dichotomy. They found that plaques associated with ACS differ
strikingly from those typically associated with stable
angina21 by being lipid laden, remarkably acellular, and
covered by thin fibrous caps prone to rupture. Activated
macrophages in the shoulder regions of such plaques precipitate
plaque rupture mediated by activation of MMPs.7 Rupture
precipitates intramural hemorrhage and thrombosis, luminal
compression and obstruction,
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