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Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

ABSTRACT: Serine proteases and G-protein-coupled receptors have been studied extensively as effectors of cell death. However, their roles in myocardial infarction have not been determined. In this study, we investigated the influence of the plasminogen activator system involving urokinase and urokinase receptor on necrosis after acute myocardial infarction. Myocardial infarction and reperfusion were induced in mouse hearts using the in vitro Langendorff model. DNA fragmentation and cleaved caspase-3 activity in urokinase- (uPA^-/-) and urokinase receptor-knockout mice (uPAR^-/-) were determined and compared with those in wild-type mice using in situ nick-end DNA labeling (TUNEL) and enzyme-linked immunosorbent assays, respectively. Infarct sizes were determined using propidium iodide and fluorescent microspheres. Following regional ischemia and reperfusion, a significant increase in the number of TUNEL-positive nuclei was observed in the ischemic zone in mouse hearts and to a lesser degree in regions remote from the ischemic area in wild-type, uPAR^-/-, and uPA^-/- groups compared with those in directly removed hearts. No significant differences were observed between uPAR^-/- and wild-type mice. Conversely, a significant reduction in DNA fragmentation was observed in ischemic and nonischemic regions after acute myocardial infarction in uPA^-/- mice when compared with that in wild-type and uPAR^-/- groups. The resulting infarct sizes were significantly smaller in uPA^-/- mice than in uPAR^-/- and wild-type mice. These data demonstrated the involvement of uPA, but not uPAR, in protecting against necrosis during acute myocardial infarction.

SUBMITTER: Herold J

PROVIDER: S-EPMC6614646 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

Herold Joerg J Heidrich Felix M FM Quick Silvio S Loehn Tobias T Ibrahim Karim K Mahlmann Adrian A Youssef Akram A

American journal of translational research 20190615 6

Serine proteases and G-protein-coupled receptors have been studied extensively as effectors of cell death. However, their roles in myocardial infarction have not been determined. In this study, we investigated the influence of the plasminogen activator system involving urokinase and urokinase receptor on necrosis after acute myocardial infarction. Myocardial infarction and reperfusion were induced in mouse hearts using the <i>in vitro</i> Langendorff model. DNA fragmentation and cleaved caspase- ...[more]

PMID: 31312373

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation 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 upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the 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 implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

Dataset Information

Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

Publications

Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

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