title: A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyperproliferative and apoptosis-resistant and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1(+/-) and Prkg1(-/-) mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093. Electronic address: rschwappacher@ucsd.edu.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Schwappacher
authors.affiliation: Institute for Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilic
authors.affiliation: University of Giessen and Marburg Lung Center, 35392 Giessen, Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: University of Giessen and Marburg Lung Center, 35392 Giessen, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Thuan
authors.initials: T
authors.lastname: Diep
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Shunhui
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gawlowski
authors.affiliation: University of Giessen and Marburg Lung Center, 35392 Giessen, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Institute for Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Boss
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Pilz
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051785:Smad Proteins; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569718:PRKG1 protein, human; C569720:Prkg1 protein, mouse; C569721:Prkg1 protein, rat; D053505:Matrix Metalloproteinases, Secreted; D006152:Cyclic GMP
keywords: Bone Morphogenetic Protein (BMP); Cyclic GMP (cGMP); Protein Kinase G (PKG); Pulmonary Hypertension; Smad Transcription Factor