Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death

Abstract

Background-Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages. Methods and Results-To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality. Conclusions-These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.

Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice

“…Both in this study and our original report (17), the fold increase in atherosclerosis was greater in SR-uPA aortic roots than on pinned aortae (compare Figs. 4 and 5).…”

“…6) had significantly increased atherosclerosis only in their aortic roots and aortic dilation in SR-uPA mice has always been limited to the root (ref. 17 and Tables 1 and 3). These observations suggest that uPA/Plg accelerates lesion progression (measurable in larger, more established aortic root lesions) but has little or no effect on lesion initiation.…”

“…These observations suggest that uPA/Plg accelerates lesion progression (measurable in larger, more established aortic root lesions) but has little or no effect on lesion initiation. If we are able to bypass the sudden death phenotype in SR-uPA mice (17) and measure aortic lesions at later time points, we anticipate finding a more pronounced effect of uPA overexpression on lesions along the entire aortic surface.…”

“…To more directly investigate the role of uPA expression by plaque macrophages, we generated transgenic mice with macrophage-targeted overexpression of uPA and bred the ''SR-uPA'' (scavenger receptor-driven uPA) transgene into the Apoe Ϫ/Ϫ background. SR-uPA Apoe Ϫ/Ϫ mice had elevated aortic uPA activity and significant two-to threefold increases in aortic atherosclerosis (17). This result supported an atherogenic role for uPA but did not identify the atherogenic mechanisms.…”

Role of multidomain structure of urokinase in regulation of growth and remodeling of vessels

“…повышенная экспрессия урокиназы и ее рецептора обнаруживается в атеросклеро-тической бляшке, что может способствовать усиленному протеолизу, обусловливающему нестабильность бляшки [123,124]. повышение экспрессии урокиназы макрофагами ускоряет прогрессирование атеросклероза и раннюю смерть трансгенных мышей [125]. помимо это-го, являясь фактором хемотаксиса для гладко-мышечных клеток, лейкоцитов и моноцитов/ макрофагов урокиназа [55,99], экспрессиро-ванная в атеросклеротической бляшке, может способствовать миграции гМк, еще большему привлечению моноцитов/макрофагов в бляшку и, таким образом, приводить к росту и «де-стабилизации» бляшки.…”