Oligonucleotide Microarrays Identified Potential Regulatory Genes Related To Early Outward Arterial Remodeling Induced By Tissue Plasminogen Activator
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PROVIDER: PRJNA522771 | ENA |
REPOSITORIES: ENA
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Project description:Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, have been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear. Plasminogen activators (PA) are involved in many of the processes of vascular remodeling. We have shown previously that increased tissue-type PA (tPA) contributes to outward vascular remodeling. To elucidate the mechanisms involved in the induction of outward remodeling we characterized changes in the expression profiles of 8799 genes in injured rat carotid arteries one and four days after recombinant tPA treatment compared to vehicle. Periadventitial tPA significantly increased lumen size and vessel area, encompassed by the external elastic lamina, at both one and four days after treatment. Among 41 differentially expressed known genes one day after tPA application, 5 genes were involved in gene transcription, 5 genes were related to the regulation of vascular tone (for example, thromboxane A2 receptor (D32080) or nonselective-type endothelin receptor (S65355)), and 8 genes were identified as participating in vascular innervation (for example, calpain (D14478) or neural cell adhesion molecule L1 (X59149)). Four days after injury in tPA-treated arteries, 4 genes, regulating vascular tone, were differentially expressed. Thus, tPA promotes outward arterial remodeling after injury, at least in part, by regulating expression of genes in the vessel wall related to function of the nervous system and vascular tone.
2019-02-16 | GSE126627 | GEO
Project description:Constrictive vascular remodeling limiting blood flow, as well as compensatory outward remodeling, has been observed in many cardiovascular diseases; however, the underlying mechanisms regulating the remodeling response of the vessels remain unclear. Plasminogen activators (PA) are involved in many of the processes of vascular remodeling. We have shown previously that increased levels of tissue-type PA (tPA) contributes to outward vascular remodeling. To elucidate the mechanisms involved in the induction of outward remodeling we characterized changes in the expression profiles of 8799 genes in injured rat carotid arteries 1 and 4 days after recombinant tPA treatment compared to vehicle. Periadventitial tPA significantly increased lumen size and vessel area, encompassed by the external elastic lamina, at both one and 4 days after treatment. Among 41 differentially expressed known genes 1 day after tPA application, five genes were involved in gene transcription, five genes were related to the regulation of vascular tone [for example, thromboxane A2 receptor (D32080) or non-selective-type endothelin receptor (S65355)], and eight genes were identified as participating in vascular innervation [for example, calpain (D14478) or neural cell adhesion molecule L1 (X59149)]. Four days after injury in tPA-treated arteries, four genes, regulating vascular tone, were differentially expressed. Thus, tPA promotes outward arterial remodeling after injury, at least in part, by regulating expression of genes in the vessel wall related to function of the nervous system and vascular tone.
| S-EPMC6502959 | biostudies-literature
Project description:HDX-MS of urokinase plasminogen activator in single-chain vs two-chain forms
2022-10-28 | MSV000090611 | MassIVE
Project description:SMCs express plasminogen activator inhibitor-1 (PAI-1), which regulates SMC function and vascular remodeling. However, whether PAI-1 controls SMC cytoskeletal dynamics and stiffness is unknown, and the causal role of PAI-1 in arterial stiffening is undefined. SMCs from human coronary arteries and aortae of wild-type vs. PAI-1-deficient mice were cultured with or without PAI-039, a specific PAI-1 inhibitor, after which cell stiffness was measured by atomic force microscopy, filamentous actin structures were assessed by confocal microscopy, and the activities cofilin, LIM domain kinase 1 (LIMK), slingshot homolog 1 (SSH), and AMP-activated protein kinase (AMPK) were measured. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. Effects of PAI-039 on aortic stiffness were assessed by pulse wave velocity. PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by significant decreases in cytoplasmic actin filaments. Similar effects were observed in wild-type, but not in PAI-1-deficient SMCs. Mechanistically, PAI-039 significantly increased the activity of cofilin, an actin depolymerase, in SMCs expressing PAI-1, but not in PAI-1-deficient cells. PAI-039 had no significant effects on LIMK or SSH activity. RNA-sequencing analysis suggested that PAI-039 up-regulates AMPK signaling in SMCs, which was confirmed by western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness without significantly altering peri-aortic fibrosis. PAI-039 decreases intrinsic SMC stiffness by reducing cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacologic inhibition of PAI-1 has potential to treat cardiovascular diseases mediated by accelerated arterial stiffening.
2023-02-23 | GSE225644 | GEO
Project description:Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasivity. The Plasminogen Activation system (PAs), including urokinase (uPA), its receptor (uPAR), and its inhibitor (PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non proteolytic modulation of cell adhesion and migration. Thus, Snail and PAs both influence those processes and are over-expressed in cancers. In this study we aimed to determine first whether Snail activity is correlated with PAs components expression and second how this correlation can influence tumoral cell migration. Keywords: Tumoral migration
2008-12-31 | GSE10395 | GEO
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.
2011-05-03 | GSE29028 | GEO
Project description:Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasivity. The Plasminogen Activation system (PAs), including urokinase (uPA), its receptor (uPAR), and its inhibitor (PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non proteolytic modulation of cell adhesion and migration. Thus, Snail and PAs both influence those processes and are over-expressed in cancers. In this study we aimed to determine first whether Snail activity is correlated with PAs components expression and second how this correlation can influence tumoral cell migration. Keywords: Tumoral migration Comparison the invasive breast cancer cell-line MDA-MB-231 expressing Snail (MDA-Neo) with its derived clone expressing a dominant negative form of Snail (Snail-DN). Expression of PAs mRNAs was performed by cDNA microarrays and real time quantitative RT-PCR. Wound healing assay was used to determine cell migration. PAI-1â??s distribution was assessed by immunostaining.
2010-06-24 | E-GEOD-10395 | biostudies-arrayexpress
Project description:HDX-MS data revealing long-range allostery that affects the catalytic activity of the serine protease, murine urokinase plasminogen activator. The allostery is mediated by the disordered region connecting the N-terminal EGF and kringle domains to the protease domain.
2024-02-06 | MSV000094027 | MassIVE
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.
2011-05-03 | E-GEOD-29028 | biostudies-arrayexpress
Project description:Plasminogen, the zymogen of plasmin, is a glycoprotein involved in fibrinolysis and a wide variety of other physiological processes. Plasminogen dysregulation has been implicated in a range of diseases. Classically, human plasminogen is categorized into two types based on the presence (type I) or absence (type II) of a single N-linked glycan, supposedly having different functional features. Using high-resolution native mass spectrometry (native MS), we uncover that the proteoform profiles of plasminogen (and plasmin) are substantially more extensive than this simple binary classification. In samples derived from human plasma, we identified up to 14 distinct proteoforms of human plasminogen, including a novel, highly abundant phosphorylation site at Ser339. To elucidate potential functional effects of these post-translational modifications, we performed proteoform-resolved kinetic analyses of the plasminogen-to-plasmin conversion using a canonical activator. This conversion is thought to involve at least two independent cleavage events: one to remove the N-terminal peptide, and another to form the active catalytic site. Our analyses reveal that these processes are not independent but are instead tightly regulated and occur in a step-wise order. Notably, N-terminal cleavage at the canonical site (Lys77) does not occur directly from intact plasminogen. Instead, an activation intermediate corresponding to cleavage at Arg68 is initially produced, which only then is further processed to the canonical Lys77 product. Based on our results, we propose a new categorization system for human plasminogen isoforms. This work highlights the capacity of high-resolution native MS to reveal new aspects of structure, even in frequently-studied serum glycoproteins.
2024-05-24 | PXD042225 | Pride