Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator

Abstract

Human hearts with end-stage failure and fibrosis have macrophage accumulation and elevated plasminogen activator activity. However, the mechanisms that link macrophage accumulation and plasminogen activator activity with cardiac fibrosis are unclear. We previously reported that mice with macrophage-targeted overexpression of urokinase plasminogen activator (SR-uPA Cardiac fibrosis, the accumulation of excess extracellular matrix in the heart, is a common feature of end-stage heart disease independent of etiology. Cardiac fibrosis may contribute to impaired systolic and diastolic function and is associated with both atrial and ventricular arrhythmias (1, 2). Fibrotic cardiac tissue is relatively avascular (3), and cardiac fibroblasts are unable to propagate cardiac action potentials (for review see Ref. 4). For these reasons, cardiac fibrosis will likely interfere with implementation of cell-based therapies for heart disease (5). Despite the importance of cardiac fibrosis, the mechanisms through which it develops are incompletely understood.Human and animal studies suggest that both macrophage accumulation and increased plasminogen activator (PA) 2 activity contribute to the pathogenesis of cardiac fibrosis. Macrophage accumulation is present in fibrotic, end-stage human hearts (6, 7). Macrophages express urokinase-type plasminogen activator (uPA) (8), and increased PA activity is present, along with macrophages and fibrosis, in failing human hearts (9). Mice with increased macrophage PA activity have early cardiac macrophage accumulation and develop cardiac fibrosis later in life (10). Moreover, mice that lack uPA are resistant to the development of cardiac fibrosis (11, 12).The pathways through which macrophage accumulation and increased cardiac PA activity could lead to cardiac fibrosis in both mice and humans are unknown. These pathways could include PA-mediated conversion of plasminogen to plasmin. Alternatively, cardiac fibrosis could be caused by plasminogen-independent actions of either PAs or macrophages. Definition of the pathways through which increased cardiac macrophage accumulation and PA activity lead to cardiac fibrosis may clarify the basic mechanisms of cardiac fibrosis and suggest new therapeutic approaches.Here we report the use of mice with macrophage-targeted expression of uPA (SR-uPA ϩ/o mice (13)) to investigate the mechanisms through which increased macrophage PA activity causes cardiac macrophage accumulation and fibrosis. SR-uPA ϩ/o mice are an appropriate animal model for these investigations because, in the absence of infarction or any other overt cardiac injury, they develop cardiac macrophage accumulation by 5 weeks of age and cardiac fibrosis by 15 weeks (10). We hypothesized that the uPA receptor (uPAR) (which can facilitate cell migration by focusing uPA and plasmin proteolytic activity to the leading edge of migrating cells (14)) is required for both cardiac macrophage accumulation and the subsequent development of fibrosis in SR-uPA

Plasminogen Activator Inhibitor-1 Deficiency Augments Visceral Mesothelial Organization, Intrapleural Coagulation, and Lung Restriction in Mice with Carbon Black/Bleomycin–Induced Pleural Injury

“…Consistent with the findings we now report, Hertig and colleagues (30) reported that PAI-1 deficiency exacerbated fibrosis in a glomerular nephritis mouse model. Our findings are also consistent with those in cardiac injury, in which incremental uPA or decremental PAI-1 fosters cardiac fibrosis (31,32). Our data indicate that PAI-1 deficiency potentiates CBB-mediated pleural injury by exacerbating visceral pleural organization sufficient to worsen lung restriction.…”

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

“…For RA and possibly for osteoarthritis, my coinvestigators and I as well as other investigators have argued that uPA may be a therapeutic target, provided that the possible complication of persistent fibrin upon its blockade does not occur (1)(2)(3)9,24). Its inhibition may also have benefit, for example, in cancer metastasis (25), cardiac fibrosis (26), and lung inflammation (27). What is sorely needed for an understanding of the biology and pathology associated with the PA/plasmin system are potent and highly specific inhibitors of the PA activities that have the appropriate pharmacokinetics.…”

Urokinase and its receptors in chronic kidney disease

“…Following bleomycin administration, the degree of hemorrhage and inflammation is reduced in uPAR−/− mice but no difference in fibrosis was detected compared with uPAR+/+ mice (113). In the heart uPAR deficiency does not prevent the fibrogenic effects of uPA-over-expression (126). While a large majority of the cellular and molecular mediators of fibrosis elicit similar effects in all of these organs, the uPA-uPAR family is a clear exception which highlights the need to carefully elucidate mechanisms of fibrosis under a variety of pathological states.…”