Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Abstract

Data from clinical studies, cell culture, and animal models implicate the urokinase plasminogen activator (uPA)/uPA receptor (uPAR)/plasminogen system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/uPAR/plasminogen stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression and mice genetically deficient in uPAR to elucidate mechanisms of uPA/uPAR/plasminogen-accelerated atherosclerosis and aneurysm formation. We found that macrophage-specific uPA overexpression accelerates atherosclerosis and causes aortic root dilation in fat-fed Ldlr ؊/؊ mice (as we previously reported in Apoe ؊/؊ mice). Macrophage-expressed uPA accelerates atherosclerosis by stimulation of lesion progression rather than initiation and causes disproportionate lipid accumulation in early lesions. uPA-accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR. In the absence of uPA overexpression, however, uPAR contributes modestly to both atherosclerosis and aortic dilation. Microarray studies identified S100A8 and S100A9 mRNA as the most highly up-regulated transcripts in uPA-overexpressing macrophages; up-regulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also up-regulated in the aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is up-regulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Macrophage microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm in a second animal model that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also reveal uPAR independence of these actions and implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.Atherosclerosis and aneurysm formation are common cardiovascular diseases that have a significant impact on human health. Atherosclerosis is characterized by accumulation in the inner blood vessel wall of cellular and matrix-rich plaques that cause vessel lumen narrowing and tissue ischemia. Clinical events in patients with atherosclerosis (e.g. heart attacks and strokes) are typically caused by rupture of atherosclerotic plaques with superimposed thrombosis that occludes the vessel lumen (1). In contrast, aneurysms are abnormal expansions of a blood vessel that can lead to complete disruption of the vessel wall, causing sudden death (2). The molecular mechanisms that contribute to plaque growth, plaque rupture, and aneurysm formation are incompletely understood. Elucidation of these mechanisms should enable the development of novel, targeted therapies that improve human health.We and others (3) have hypothesized that the urokinase plasminogen activator (uPA) 6 /plasminoge...

Apoptosis, proliferation, and morphology during vein graft remodeling in rabbits

“…In addition, the shear stress acting on the vein may have increased. These physical and chemical factors could have resulted in apoptosis and stimulated VSMCs in the vessel walls to migrate to the intima (Farris et al, 2011). This may explain the early apoptosis and decline in tunica medial-adventitial thickness observed in the present work following transplantation.…”

“…Farris et al (2011) observed that plasminogen activators, particularly urinary plasminogen activator (uPA), and their receptors play significant roles in vein graft restenosis (Castro and Tanus-Santos, 2013). uPA also facilitates the expression of matrix metalloproteinases (MMPs).…”

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

“…42 In a mouse transgenic model, macrophage-specific uPA overexpression accelerated atherosclerosis by stimulation of lesion progression and accumulation of lipids in early lesions, and these effects were largely independent of uPAR. 43 However, in the absence of uPA overexpression, uPAR contributed modestly to atherosclerosis. Our study suggests that the uPA-uPAR interaction may be an important contributor to atherogenesis, and the increased serum PON1 activity and decreased oxidative stress shown in uPAR Ϫ/Ϫ mice could account, at least in part, for the reported resistance of low-density lipoprotein receptor Ϫ/Ϫ / uPAR Ϫ/Ϫ double knockout mice to high-fat diet-induced atherosclerosis.…”

“…Our study suggests that the uPA-uPAR interaction may be an important contributor to atherogenesis, and the increased serum PON1 activity and decreased oxidative stress shown in uPAR Ϫ/Ϫ mice could account, at least in part, for the reported resistance of low-density lipoprotein receptor Ϫ/Ϫ / uPAR Ϫ/Ϫ double knockout mice to high-fat diet-induced atherosclerosis. 43 In summary, this study has important implications for understanding the ability of uPA to modulate oxidative stress, and it gives more insight into the influence of uPA on atherogenesis. .…”

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

“…Animals were fed a western high-fat diet to develop complex atherosclerotic plaques in the sinus of Valsalva of the aorta. Previously, it has been shown that apolipoprotein E deficient and LDLR -/ -mice have significantly more calcified aortic areas than nontransgenic mice [29] and that uPAR is atherogenic in nontransgenic LDLR -/ -mice [30]. Furthermore, it was demonstrated that uPAR deficiency results in impaired vascular inflammation and remodeling [23,31].…”