title: Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension.
abstract: Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1-3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1(-/-) mice were protected against the development and progression of chronic HPH, whereas Akt2(-/-) mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1(-/-) mice, with no significant effect noted in the Akt2(-/-) mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Fraidenburg
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Shanshan
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Drennan
authors.affiliation: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.affiliation: Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona;
authors.forename: Ayako
authors.initials: A
authors.lastname: Makino
authors.affiliation: Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and jasonyuan@email.arizona.edu.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D017380:Hypertrophy, Right Ventricular; D000860:Hypoxia / Q000473:pathology*; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011651:Pulmonary Artery / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D066253:Vascular Remodeling; D014655:Vascular Resistance
chemical_list: D034741:RNA, Small Interfering; D013629:Tamoxifen; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Akt/mammalian target of rapamycin signaling; hypoxia; pulmonary vascular remodeling; smooth muscle cell proliferation