Platelets synthesize large amounts of active plasminogen activator inhibitor 1

Brogren, Helén; Karlsson, Lena; Andersson, Maria; Wang, Lingwei; Erlinge, David; Jern, Sverker

doi:10.1182/blood-2004-04-1439

Cited by 197 publications

(150 citation statements)

References 35 publications

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“…To verify this hypothesis, ECs were exposed to hypoxia for 24 hours, and puromycin, a synthetic inhibitor of protein synthesis, was added for the indicated time to block new synthesis of ILK and to examine the pure effect of intrinsic stabilization, as shown in previous reports. 13 The level of ILK, shown by Western blot, significantly increased in hypoxic HUVECs compared with normoxic HUVECs despite puromycin treatment ( Figure 2B), which suggests that ILK was stabilized under hypoxic conditions.…”

Section: Ilk Is Stabilized In Hypoxia By Heat Shock Protein 90mentioning

confidence: 96%

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

et al. 2006

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Background-Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) isessential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell-derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-B and hypoxia-inducible factor-1␣ and induces recruitment of EPCs to ischemic areas. Methods and Results-Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock protein 90. ILK overexpression in normoxic ECs resulted in ICAM-1 and SDF-1 upregulation through dual control by nuclear factor-B and hypoxia-inducible factor-1␣. Blockade of ILK in hypoxic ECs significantly abrogated the expression of both molecules, which led to decreased EPC incorporation into ECs. A hindlimb ischemia model showed that ILK blockade significantly reduced EPC homing to ischemic limb and consequently led to poor neovascularization. Overexpression of ILK in the Matrigel plug significantly improved neovascularization in vivo, whereas the blockade of ILK resulted in the opposite effect. Conclusions-Endogenous

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Section: Ilk Is Stabilized In Hypoxia By Heat Shock Protein 90mentioning

confidence: 96%

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

et al. 2006

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“…Furthermore, activated platelets induce tissue factor (TF) expression in human endothelial and smooth muscle cells, presumably by releasing soluble mediators such as serotonin and PDGF (72). Platelets also synthesise plasminogen activator inhibitor (PAI)-1, a main regulator of fibrinolysis (73).…”

Section: Platelet Micrornamentioning

confidence: 99%

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Müller¹,

Chatterjee²,

Rath³

et al. 2015

Thromb Haemost

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SummaryPlatelets play a pivotal role in chronic inflammation leading to progression of atherosclerosis and acute coronary events. Recent discoveries on novel mechanisms and platelet-dependent inflammatory targets underpin the role of platelets to maintain a chronic inflammatory condition in cardiovascular disease. There is strong and clinically relevant crosslink between chronic inflammation and platelet activation. Antiplatelet therapy is a cornerstone in the prevention and treatment of acute cardiovascular events. The benefit of antiplatelet agents has mainly been attributed to their direct anti-aggregatory impact. Some anti-inflammatory off-target effects have also been described. However, it is unclear whether these effects are secondary due to inhibition of platelet activation or are caused by direct distinct mechanisms interfering with inflammatory pathways. This article will highlight novel platelet associated targets that contribute to inflammation in cardiovascular disease and elucidate mechanisms by which currently available antiplatelet agents evolve anti-inflammatory capacities, in particular by carving out the differential mechanisms directly or indirectly affecting platelet mediated inflammation. It will further illustrate the prognostic impact of antiplatelet therapies by reducing inflammatory marker release in recent cardiovascular trials.

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“…7). One potential source of PAI-1 is platelets, which release preformed PAI-1 upon stimulation with thrombin (Brogren et al, 2004). Together, the data indicate that enhanced PAI-1 appearance in LPS/RANtreated rats is mediated through both transcription-dependent and -independent mechanisms, the latter occurring during coagulation.…”

Section: Coagulation and Gene Expression In Lps/ran Hepatotoxicity 639mentioning

confidence: 58%

Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine

Luyendyk¹,

Lehman‐McKeeman²,

Nelson³

et al. 2006

J Pharmacol Exp Ther

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In an animal model of drug idiosyncrasy, rats cotreated with nonhepatotoxic doses of lipopolysaccharide (LPS) and ranitidine (RAN) develop hepatocellular injury, whereas rats treated with LPS and famotidine (FAM) do not. The coagulation system and neutrophils (PMNs) are requisite mediators of LPS/RANinduced liver injury. We tested the hypothesis that unique gene expression in LPS/RAN-treated rats requires coagulation system activation and that these changes are absent in rats given LPS and FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 ϫ 10 6 endotoxin units/kg i.v.) or its vehicle, and then 1 h later, they were treated with heparin (3000 U/kg) or its vehicle. One hour thereafter, they were given RAN (30 mg/kg), FAM (6 mg/kg, a pharmacologically equiefficacious dose, or 28.8 mg/kg, an equimolar dose), or vehicle (i.v.). They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity, coagulation system activation, and liver gene expression (2 h only). Statistical filtering of gene array results and real-time polymerase chain reaction identified groups of genes expressed in LPS/RAN-treated rats but not LPS/FAM-treated rats that were either changed or unchanged by heparin administration. For example, LPS/RAN-induced mRNA expression of the inflammatory mediators interleukin-6, cyclooxygenase-2, and macrophage inflammatory protein-2 (MIP-2) was reduced by anticoagulation. Enhancement of serum MIP-2 and plasminogen activator inhibitor-1 concentrations in LPS/RAN-treated rats was prevented by anticoagulation. The results suggest cross-talk between hemostasis-induced gene expression and inflammation (e.g., PMN function) in the genesis of hepatocellular injury in LPS/RAN-treated rats. In contrast, neither the expression of such genes nor hepatocellular necrosis occurred in rats treated with LPS/FAM.Idiosyncratic drug reactions are adverse responses that occur in a small fraction of people taking a drug, and the liver is a frequent target organ. The unpredictable nature and severity of idiosyncratic liver injury have significant impact both on human health and the pharmaceutical industry. Although numerous studies have proposed that idiosyncratic hepatotoxicity occurs as a consequence of metabolic polymorphism and/or drug-specific immunity (for reviews, see Pirmohamed et al., 1996;Ju and Uetrecht, 2002), for the majority of drugs, the mechanisms underlying idiosyncratic responses are unclear. Recent studies have suggested that an inflammatory response might precipitate idiosyncratic liver injury from some drugs, and animal models have been developed to examine drug-inflammation interaction (Buchweitz et al., 2002;Luyendyk et al., 2003b;Roth et al., 2003).The histamine2 (H2)-receptor antagonist ranitidine (RAN)

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Platelets synthesize large amounts of active plasminogen activator inhibitor 1

Cited by 197 publications

References 35 publications

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine

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