Identification of differentially expressed genes induced by transient ischemic stroke

Schwarz, David; Barry, Guy; Mackay, Kenneth B.; Manu, Frank; Naeve, Gregory S.; Vana, Alicia M; Verge, Gail; Conlon, Paul; Foster, Alan C.; Maki, Richard A.

doi:10.1016/s0169-328x(02)00135-3

Cited by 56 publications

(40 citation statements)

References 32 publications

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“…The 28-kDa fragment could act as either an agonist or an antagonist for fulllength CCN1 in a cell type-and context-specific fashion because CCN1 interacts with specific integrins in specific cell types, either requiring the CT domain or independent of the CT domain (12,20,42,43). Because several pathologic conditions are associated with up-regulation of CCN1 (45,(49)(50)(51) and many cell types express the PA/plasmin system, which could be upregulated further by pathologic conditions (33,(52)(53)(54), it is likely that the truncated CCN1 fragments would be generated in vivo. If so, the 28-kDa fragment of CCN1 may serve as a marker for pathogenesis of disease, particularly cancer and cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Proteolysis of CCN1 by Plasmin: Functional Implications

et al. 2005

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Plasmin is shown to play a crucial role in many pathophysiologic processes primarily through its ability to degrade extracellular matrix (ECM) and/or mobilizing growth factors that are sequestered in the ECM. Cysteine-rich 61 (CCN1) is a matricellular protein of which expression is up-regulated in cancer and various vascular diseases. The present study was undertaken to investigate whether plasmin liberates CCN1 from the ECM and whether the released growth factor modulates endothelial cell migration. Treatment of breast carcinoma cells (MDA-MB-231) with plasmin released a truncated form of CCN1 (28 kDa) into the overlying medium. Experiments with recombinant CCN1 confirmed that plasmin effectively cleaves CCN1. Thrombin and other clotting/fibrinolytic proteases are ineffective in cleaving CCN1. Further studies revealed that the conditioned medium of plasmintreated carcinoma cells supports endothelial cell migration and that antibodies specific to CCN1 blocked this enhancing effect. These data were the first to show that plasmin can liberate a pluripotent matrix signaling protein, CCN1, from the ECM. Because both CCN1 and the components of the plasmin generation system are present in tumor cells and a variety of other cells, the proteolysis of CCN1 by plasmin may play a role in many pathophysiologic processes, including tumor cellmediated angiogenesis. (Cancer Res 2005; 65(21): 9705-11)

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Section: Discussionmentioning

confidence: 99%

Proteolysis of CCN1 by Plasmin: Functional Implications

et al. 2005

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“…18 In a rat middle cerebral artery occlusion (MCAO) model, LOX-1 expression was increased at a transient ischemic core site. 19 Evidence suggests that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. 19 Importantly, plasma L5 levels are elevated in patients with risk factors for stroke, including type 2 diabetes, hypercholesterolemia, and smoking.…”

Section: Introductionmentioning

confidence: 99%

Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation

Shen

Chen

Hsu

et al. 2016

Blood

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Key Points• L5 is elevated in ischemic stroke patients, and its receptor, LOX-1, plays a critical role in increasing stroke size.• L5 induces platelet secretion of Ab to potentiate platelet activation and aggregation via LOX-1 and IKK2.L5, the most electronegative and atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients and examined whether lectin-like oxidized LDL receptor-1 (LOX-1), the receptor for L5 on endothelial cells and platelets, plays a critical role in stroke. Because amyloid b (Ab) stimulates platelet aggregation, we studied whether L5 and Ab function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Ab, and platelet LOX-1 expression were significantly higher in acute ischemic stroke patients than in controls without metabolic syndrome (P < .01). In mice subjected to focal cerebral ischemia, L5 treatment resulted in larger infarction volumes than did phosphatebuffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefold after focal cerebral ischemia in mice, illustrating the importance of LOX-1 in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Ab release via IkB kinase 2 (IKK2). Furthermore, L51Ab synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IkBa, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-kB (NF-kB). Injecting L51Ab shortened tail-bleeding time by 50% (n 5 12; P < .05 vs L1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Abmediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-kB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies. (Blood. 2016;127(10):1336-1345

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“…Another proapoptotic member of this family, Atf3, was strongly induced already at 2 hours after HI, and remained upregulated at all time points examined. Atf3 has previously been shown to be upregulated after ischemia in the adult brain (Ohba et al, 2003;Schwarz et al, 2002). Atf3 is induced after DNA damage, and overexpression of this protein slows down progression of cells from G1 to S phase (Fan et al, 2002).…”

Section: Genes Related To Apoptotic/cell Deathmentioning

confidence: 99%

“…Several studies have been performed studying changes in gene expression after ischemia in the adult brain using microarrays (Jin et al, 2001;Kim et al, 2002;Lu et al, 2003;Raghavendra Rao et al, 2002;Schmidt-Kastner et al, 2002;Schwarz et al, 2002;Tang et al, 2002), showing many new genes of interest. Many studies have, however, been limited to study the gene expression in a certain region at one specific time point (Kim et al, 2002;Lu et al, 2003;Schmidt-Kastner et al, 2002).…”

mentioning

confidence: 99%

Global Gene Expression in the Immature Brain after Hypoxia-Ischemia

Hedtjärn¹,

Mallard²,

Eklind

et al. 2004

J Cereb Blood Flow Metab

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Summary:Ischemia induces a complex response of differentially expressed genes in the brain. In order to understand the specific mechanisms of injury in the developing brain, it is important to obtain information on global changes in the transcriptome after neonatal hypoxia-ischemia. In this study, oligonucleotide arrays were used to investigate genomic changes at 2, 8, 24, and 72 hours after neonatal hypoxia-ischemia, which was induced in 9-day-old mice by left carotid artery ligation followed by hypoxia (10% O 2 ). In total, 343 genes were differentially expressed in cortex, hippocampus, thalamus, and striatum 2 to 72 hours after hypoxia-ischemia, when comparing ipsilateral with contralateral hemispheres and with controls, using the significance analysis for microarrays. A total of 283 genes were upregulated and 60 were downregulated, and 94% of the genes had not previously been shown after neonatal hypoxia-ischemia. Genes related to transcription factors and metabolism had mostly upregulated transcripts, whereas most downregulated genes belonged to the categories of ion and vesicular transport and signal transduction. Genes involved in transcription, stress, and apoptosis were induced early after the insult, and many new genes that may play important roles in the pathophysiology of neonatal hypoxiaischemia were identified.

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Identification of differentially expressed genes induced by transient ischemic stroke

Cited by 56 publications

References 32 publications

Proteolysis of CCN1 by Plasmin: Functional Implications

Proteolysis of CCN1 by Plasmin: Functional Implications

Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation

Global Gene Expression in the Immature Brain after Hypoxia-Ischemia

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