title: PKG-1α leucine zipper domain defect increases pulmonary vascular tone: implications in hypoxic pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is a chronic disease characterized by a progressive increase in vasomotor tone, narrowing of the vasculature with structural remodeling, and increase in pulmonary vascular resistance. Current treatment strategies include nitric oxide therapy and methods to increase cGMP-mediated vasodilatation. cGMP-dependent protein kinases (PKG) are known mediators of nitric oxide- and cGMP-induced vasodilatation. Deletion of PKG-1 in mice has been shown to induce PH, however, the exact mechanisms by which loss of PKG-1 function leads to PH is not known. In a mouse model with a selective mutation in the NH2-terminus leucine zipper protein interaction domain of PKG-1α [leucine zipper mutant (LZM)], we found a progressive increase in right ventricular systolic pressure and right heart hypertrophy compared with wild-type (WT) mice and increased RhoA-GTPase activity in the lungs. When exposed to chronic hypoxia, LZM mice developed modestly enhanced right ventricular remodeling compared with WT mice. Tadalafil, a phosphodiesterase-5 inhibitor that increases cGMP levels, significantly attenuated hypoxia-induced cardiopulmonary remodeling in WT mice but had no effect in LZM mice. We conclude that a functional leucine zipper domain in PKG-1α is essential for maintenance of a low pulmonary vascular tone in normoxia and for cGMP-mediated beneficial effects of phosphodiesterase-5 inhibition in hypoxic cardiopulmonary remodeling.
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and ramchan@uic.edu.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Ramchandran
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and.
authors.forename: Aarti
authors.initials: A
authors.lastname: Raghavan
authors.affiliation: Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois.
authors.forename: David
authors.initials: D
authors.lastname: Geenen
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and.
authors.forename: Miranda
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Bach
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois; and.
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D011652:Pulmonary Circulation / Q000187:drug effects; D000068581:Tadalafil; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D002243:Carbolines; D014665:Vasodilator Agents; D000068581:Tadalafil; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569720:Prkg1 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: hypoxia; leucine zipper mutant guanosine 3′,5′-cyclic monophosphate-dependent protein kinase; phosphodiesterases; pulmonary hypertension and right ventricular hypertrophy