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The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.

ABSTRACT: Cardiac plasmin activity is increased following myocardial ischemia. To test the hypothesis that macrophage-derived uPA is a key mediator of repair following myocardial infarction, we performed myocardial infarction on mice with macrophage-specific over-expression of uPA (SR-uPA mice). SR-uPA(+/0) mice and wild-type littermates were sacrificed at 5 days or 4 weeks after infarction and cardiac content of macrophages, collagen, and myofibroblasts was quantified. Cardiac function and dimensions were assessed by echocardiography at baseline and at 4 weeks post-infarction. At 4 weeks after myocardial infarction, macrophage counts were increased in SR-uPA(+/0) mice in the infarct (13.1 vs. 4.9%, P<0.001) and distant uninfarcted regions (5.9 vs. 2.4%, P<0.001). Infarct scar was thicker in SR-uPA(+/0) mice (0.54+/-0.03 mm vs. 0.45+/-0.03 mm, P<0.05) and infarct cardiac collagen content was increased (72.4+/-3.3% vs. 63.0+/-3.6%, P<0.06). Functionally, these changes resulted in mildly improved fractional shortening in SR-uPA(+/0) mice compared to controls (24.6+/-1.68 vs. 19.8+/-1.3%, P=0.03). At 5 days after infarction there was increased collagen content in the scar without increases in macrophages or myofibroblasts. To understand the mechanisms by which macrophage-derived uPA increases collagen, cardiac fibroblasts were treated with macrophage-conditioned medium or plasmin and expression of ColIalpha1 measured by qPCR. Conditioned media from SR-uPA(+/0) or plasmin-treated non-transgenic macrophages but not plasmin alone increased collagen expression in isolated cardiac fibroblasts. We hypothesize that plasmin generation in the heart in response to injury may induce activation of macrophages to a profibrotic phenotype to allow rapid formation of collagenous scar.

SUBMITTER: Minami E

PROVIDER: S-EPMC3041515 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.

Minami Elina E Castellani Chiara C Malchodi Laura L Deem Jennifer J Bertko Kate K Meznarich Jessica J Dishmon Monja M Murry Charles E CE Stempien-Otero April A

Journal of molecular and cellular cardiology 20100407 3

Cardiac plasmin activity is increased following myocardial ischemia. To test the hypothesis that macrophage-derived uPA is a key mediator of repair following myocardial infarction, we performed myocardial infarction on mice with macrophage-specific over-expression of uPA (SR-uPA mice). SR-uPA(+/0) mice and wild-type littermates were sacrificed at 5 days or 4 weeks after infarction and cardiac content of macrophages, collagen, and myofibroblasts was quantified. Cardiac function and dimensions wer ...[more]

PMID: 20380835

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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.

Project description:Several post-translational modifications figure prominently in ventricular remodeling. The beta-O-linkage of N-acetylglucosamine (O-GlcNAc) to proteins has emerged as an important signal in the cardiovascular system. Although there are limited insights about the regulation of the biosynthetic pathway that gives rise to the O-GlcNAc post-translational modification, much remains to be elucidated regarding the enzymes, such as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which regulate the presence/absence of O-GlcNAcylation. Recently, we showed that the transcription factor, E2F1, could negatively regulate OGT and OGA expression in vitro. The present study sought to determine whether E2f1 deletion would improve post-infarct ventricular function by de-repressing expression of OGT and OGA. Male and female mice were subjected to non-reperfused myocardial infarction (MI) and followed for 1 or 4 week. MI significantly increased E2F1 expression. Deletion of E2f1 alone was not sufficient to alter OGT or OGA expression in a naïve setting. Cardiac dysfunction was significantly attenuated at 1-week post-MI in E2f1-ablated mice. During chronic heart failure, E2f1 deletion also attenuated cardiac dysfunction. Despite the improvement in function, OGT and OGA expression was not normalized and protein O-GlcNAcyltion was not changed at 1-week post-MI. OGA expression was significantly upregulated at 4-week post-MI but overall protein O-GlcNAcylation was not changed. As an alternative explanation, we also performed guided transcriptional profiling of predicted targets of E2F1, which indicated potential differences in cardiac metabolism, angiogenesis, and apoptosis. E2f1 ablation increased heart size and preserved remote zone capillary density at 1-week post-MI. During chronic heart failure, cardiomyocytes in the remote zone of E2f1-deleted hearts were larger than wildtype. These data indicate that, overall, E2f1 exerts a deleterious effect on ventricular remodeling. Thus, E2f1 deletion improves ventricular remodeling with limited impact on enzymes regulating O-GlcNAcylation.

Dataset Information

The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.

Publications

The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.

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