fibrinolysis and arterial mural proteolysis
Results of recent work have highlighted the potential role of plasminogen activators and PAI-1 in the evolution of macroangiography in two compartments, blood in the arterial lumen (as described above) and in the arterial wall itself (125). Intramural plasminogen activators and PAI-1 influence proteolytic activity of matrix metalloproteinases (MMPs) that are activated from zymogens by plasmin. Cell surface plasmin-dependent proteolytic activation of MMPs promotes migration of SMCs and macrophages into the neointima and tunica media. Activation of MMPs appears to be a determinant of plaque rupture in complex atheroma and advanced atherosclerotic lesions, particularly in the vulnerable acellular shoulder regions of plaques (126).
Conversely, overexpression of PAI-1, by inhibiting intramural proteolysis and turnover of matrix, may contribute to accumulation of extracellular matrix (ECM) particularly in early atheromatous lesions. Overexpression of PAI-1 and the resultant accumulation of ECM have been implicated as a substrate for activation and migration of SMCs, chemotaxis of macrophages, and hence acceleration of early atherosclerosis. Analogously increased expression of PAI-1 has been observed in zones of early vessel wall injury after fatal pulmonary thromboembolism (127).
Taken together, these observations imply that an imbalance between the activity of plasminogen activators and the activity of PAI-1 can contribute to progression of atherosclerosis in diverse directions under diverse conditions. In early lesions, excess activity of PAI-1 may potentiate accumulation of matrix and its consequences. In complex lesions and late atherosclerosis, excess activity of plasminogen activators may exacerbate plaque rupture. Our observations regarding the relative amounts of plasminogen activators and of PAI-1 in association with the severity of atherosclerosis are consistent with both (128). The tissue content of PAI-1 is increased in early atherosclerotic lesions exemplified by fatty streaks. By contrast, the tissue content of plasminogen activators is increased in more complex lesions at a time when SMC proliferation is prominent.
The effects of PAI-1 in vessel wall repair have been clarified in animals genetically modified to be deficient in PAI-1 (PAI-1 knockout mice). Removal of noncellular debris and migration of SMCs are accelerated after mechanical or electrical injury of arteries in PAI-1-deficient mice (129). However, clot burden and persistence are increased. Thus, it appears likely that excess of either plasminogen activator or PAI-1 activity in the vessel wall may potentiate atherosclerosis. Excess PAI-1 may potentiate mural thickening secondary to accumulation of ECM and noncellular debris with diminished migration into the neointima of SMC during evolution of plaques destined to be vulnerable to rupture. Excess plasminogen activator activity may potentiate degradation of matrix and plaque rupture (125) in mature, vulnerable plaques. Consistent with this view, we have found increased immunoassayable PAI-1 and decreased urokinase plasminogen activator (uPA) in atherectomy specimens from occlusive coronary lesions in patients with diabetes with or without restenosis compared with values in corresponding specimens from non-diabetic subjects (130). Conversely, immunoassayable urokinase in the atheroma was markedly diminished in association with diabetes.
It has been demonstrated that people with type 2 diabetes are remarkably prone not only to primary coronary lesions but also to restenosis after angioplasty (6,131,132). Our recent observations with extracted atheroma suggest that restenosis, especially that following iatrogenic injury to vessel walls associated with percutaneous coronary intervention (PCI), may develop, in part, because of increased expression of PAI-1. Although increased PAI-1 attenuates cell migration, it augments proliferation and inhibits apoptosis (133). Thus, restenosis may be exacerbated by increased PAI-1 resulting in increased proliferation and decreased apoptosis of SMCs within the arterial wall.
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