title: Transforming growth factor-beta modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells.
abstract: Nitric oxide signaling has an important role in regulating pulmonary development and function. Expression of soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI), both critical mediators of nitric oxide (NO) signaling, is diminished in the injured newborn lung through unknown mechanisms. Recent studies suggest that excessive transforming growth factor-beta (TGF-beta) activity inhibits injured newborn lung development. To explore mechanisms that regulate pulmonary NO signaling, we tested whether TGF-beta decreases sGC and PKGI expression in the injured developing lung and pulmonary vascular smooth muscle cells (SMC). We found that chronic oxygen-induced lung injury decreased pulmonary sGCalpha(1) and PKGI immunoreactivity in mouse pups and that exposure to a TGF-beta-neutralizing antibody prevented this reduction of sGC and PKGI protein expression. In addition, TGF-beta(1) decreased expression of NO signaling enzymes in freshly isolated pulmonary microvascular SMC/myofibroblasts, suggesting that TGF-beta has a direct role in modulating NO signaling in the pup lung. Moreover, TGF-beta(1) decreased sGC and PKGI expression in pulmonary artery and aortic SMC from adult rats and mice, suggesting a general role for TGF-beta in modulating NO signaling in vascular SMC. Although other cytokines decrease sGC mRNA stability, TGF-beta did not modulate sGCalpha(1) or PKGIbeta mRNA turnover in vascular SMC. These studies indicate for the first time that TGF-beta decreases NO signaling enzyme expression in the injured developing lung and pulmonary vascular SMC. Moreover, they suggest that TGF-beta-neutralizing molecules might counteract the effects of injury on NO signaling in the newborn lung.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital-East, 149 13th St., Charlestown, MA 02129, USA.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Bachiller
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D002452:Cell Count; D019070:Cell Lineage / Q000187:drug effects; D002469:Cell Separation; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D021122:Protein Subunits; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; C569720:Prkg1 protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase