title: Fibronectin upregulates cGMP-dependent protein kinase type Iβ through C/EBP transcription factor activation in contractile cells.
abstract: The nitric oxide (NO)-soluble guanylate cyclase (sGC) pathway exerts most of its cellular actions through the activation of the cGMP-dependent protein kinase (PKG). Accumulation of extracellular matrix is one of the main structural changes in pathological conditions characterized by a decreased activity of this pathway, such as hypertension, diabetes, or aging, and it is a well-known fact that extracellular matrix proteins modulate cell phenotype through the interaction with membrane receptors such as integrins. The objectives of this study were 1) to evaluate whether extracellular matrix proteins, particularly fibronectin (FN), modulate PKG expression in contractile cells, 2) to analyze the mechanisms involved, and 3) to evaluate the functional consequences. FN increased type I PKG (PKG-I) protein content in human mesangial cells, an effect dependent on the interaction with β(1)-integrin. The FN upregulation of PKG-I protein content was due to increased mRNA expression, determined by augmented transcriptional activity of the PKG-I promoter region. Akt and the transcription factor CCAAT enhancer-binding protein (C/EBP) mediated the genesis of these changes. FN also increased PKG-I in another type of contractile cell, rat vascular smooth muscle cells (RVSMC). Tirofiban, a pharmacological analog of FN, increased PKG-I protein content in RVSMC and rat aortic walls and magnified the hypotensive effect of dibutyryl cGMP in conscious Wistar rats. The present results provide evidence of a mechanism able to increase PKG-I protein content in contractile cells. Elucidation of this novel mechanism provides a rationale for future pharmacotherapy in certain vascular diseases.
authors.affiliation: Dept. of Physiology, Facultad de Medicina, Universidad de Alcalá, Campus Universitario s/n, Alcalá de Henares, 28871 Madrid, Spain.
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Chamorro-Jorganes
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.forename: Marta
authors.initials: M
authors.lastname: Saura
authors.forename: Alicia
authors.initials: A
authors.lastname: Luengo
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Puyol
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D005353:Fibronectins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D005353:Fibronectins; D012333:RNA, Messenger; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human