Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase
| Autor: | Douglas B. Cines, Tatiana Lebedeva, Jing Xue, Taher Nassar, Khalil Bdeir, Abd Al-Roof Higazi, A. M. Makarova, Victoria Stepanova, Maria E. Carinato |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Endothelium
Nitric Oxide Synthase Type III Acute Lung Injury Vascular permeability Pulmonary Edema Respiratory Mucosa Lung injury Biology Biochemistry Cell Line Capillary Permeability chemistry.chemical_compound Mice Plasminogen Activator Inhibitor 1 Serpin E2 medicine Animals Humans Enzyme Inhibitors Phosphorylation Protein kinase A Molecular Biology Mice Knockout Blood-Air Barrier Fibrinolysis Blood–air barrier Cell Biology Cyclic AMP-Dependent Protein Kinases Urokinase-Type Plasminogen Activator Cell biology Nitric oxide synthase medicine.anatomical_structure NG-Nitroarginine Methyl Ester chemistry Plasminogen activator inhibitor-1 biology.protein Plasminogen activator Low Density Lipoprotein Receptor-Related Protein-1 |
| Zdroj: | The Journal of biological chemistry. 286(26) |
| ISSN: | 1083-351X |
| Popis: | Urokinase plasminogen activator (uPA) and PA inhibitor type 1 (PAI-1) are elevated in acute lung injury, which is characterized by a loss of endothelial barrier function and the development of pulmonary edema. Two-chain uPA and uPA-PAI-1 complexes (1-20 nM) increased the permeability of monolayers of human pulmonary microvascular endothelial cells (PMVECs) in vitro and lung permeability in vivo. The effects of uPA-PAI-1 were abrogated by the nitric-oxide synthase (NOS) inhibitor L-NAME (N(D)-nitro-L-arginine methyl ester). Two-chain uPA (1-20 nM) and uPA-PAI-1 induced phosphorylation of endothelial NOS-Ser(1177) in PMVECs, which was followed by generation of NO and the nitrosylation and dissociation of β-catenin from VE-cadherin. uPA-induced phosphorylation of eNOS was decreased by anti-low density lipoprotein receptor-related protein-1 (LRP) antibody and an LRP antagonist, receptor-associated protein (RAP), and when binding to the uPA receptor was blocked by the isolated growth factor-like domain of uPA. uPA-induced phosphorylation of eNOS was also inhibited by the protein kinase A (PKA) inhibitor, myristoylated PKI, but was not dependent on PI3K-Akt signaling. LRP blockade and inhibition of PKA prevented uPA- and uPA-PAI-1-induced permeability of PMVEC monolayers in vitro and uPA-induced lung permeability in vivo. These studies identify a novel pathway involved in regulating PMVEC permeability and suggest the utility of uPA-based approaches that attenuate untoward permeability following acute lung injury while preserving its salutary effects on fibrinolysis and airway remodeling. |
| Databáze: | OpenAIRE |
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