Intracellular signaling pathways involved in inhibition of PAI-1 expression by CNP in endothelial cells.
PAI-1 is a multifunctional protein stimulated by infectious agents and its activation is mediated by inflammatory cytokines such as TNFalpha. Recent studies demonstrate that natriuretic peptides, particularly C-type (CNP), can affect PAI-1 expression in bovine aortic smooth muscle cells and rat aortic endothelial cells. We have previously shown that CNP inhibits both basal and TNFalpha induced expression of PAI-1 in human endothelial cells. Herein, we describe mechanism by which CNP modulates signaling engaged in controlling PAI-1 expression in human endothelial cells. To examine which pathway initiated by TNFalpha is influenced, we tested kinase activity of MAP, PI3K/AKT and involvement of cGMP in endothelial cells exposed to CNP. CNP significantly increased cGMP level in endothelial cells. Its analogue, 8-Br-cGMP alone had no effect but significantly inhibited TNFalpha induced expression of PAI-1. Similarly, CNP and the inhibitors of ERK1/2 (PD098059) and PI3K (LY294002) attenuated PAI-1 expression induced by TNFalpha. CNP almost abolished TNFalpha induced phosphorylation of ERK1/2 but did not affect JNK phosphorylation, indicating that its effect on ERK1/2 was specific. These data suggest that CNP might function as the natural defense of vascular wall against cytokine induced PAI-1 release through its ability to inactivate PI3K/AKT and MEK/ERK pathways.
Jerczynska
H
H
Department of Molecular and Medical Biophysics, Medical University in Lodz, Lodz, Poland.
Pawlowska
Z
Z
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D045283:Natriuretic Agents / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002867:Chromones; D005419:Flavonoids; D009025:Morpholines; D016328:NF-kappa B; D045283:Natriuretic Agents; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D014409:Tumor Necrosis Factor-alpha; D020098:Natriuretic Peptide, C-Type; C016276:8-bromocyclic GMP; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006152:Cyclic GMP; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one