PMID- 25416384 OWN - NLM STAT- MEDLINE DCOM- 20150421 LR - 20211203 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 308 IP - 2 DP - 2015 Jan 15 TI - Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. PG - L208-20 LID - 10.1152/ajplung.00242.2014 [doi] AB - 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. CI - Copyright (c) 2015 the American Physiological Society. FAU - Tang, Haiyang AU - Tang H AD - 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; FAU - Chen, Jiwang AU - Chen J AD - Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; FAU - Fraidenburg, Dustin R AU - Fraidenburg DR AD - Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; FAU - Song, Shanshan AU - Song S AD - 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; FAU - Sysol, Justin R AU - Sysol JR AD - 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. FAU - Drennan, Abigail R AU - Drennan AR AD - Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; FAU - Offermanns, Stefan AU - Offermanns S AD - Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. FAU - Ye, Richard D AU - Ye RD AD - Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and. FAU - Bonini, Marcelo G AU - Bonini MG AD - Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and. FAU - Minshall, Richard D AU - Minshall RD AD - Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and. FAU - Garcia, Joe G N AU - Garcia JG AD - Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; FAU - Machado, Roberto F AU - Machado RF AD - Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; FAU - Makino, Ayako AU - Makino A AD - Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; FAU - Yuan, Jason X-J AU - Yuan JX AD - 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. LA - eng GR - HL066012/HL/NHLBI NIH HHS/United States GR - R01 HL111656/HL/NHLBI NIH HHS/United States GR - HL125208/HL/NHLBI NIH HHS/United States GR - R01 HL115014/HL/NHLBI NIH HHS/United States GR - HL 115014/HL/NHLBI NIH HHS/United States GR - HL082547/HL/NHLBI NIH HHS/United States GR - R01 HL127342/HL/NHLBI NIH HHS/United States GR - U01 HL125208/HL/NHLBI NIH HHS/United States GR - R01 HL066012/HL/NHLBI NIH HHS/United States GR - P01 HL060678/HL/NHLBI NIH HHS/United States GR - HL098053/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141121 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (RNA, Small Interfering) RN - 094ZI81Y45 (Tamoxifen) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Akt2 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, mouse) SB - IM MH - Animals MH - Blood Pressure/genetics/physiology MH - Cell Movement MH - Cell Proliferation MH - Humans MH - Hypertension, Pulmonary/*genetics MH - Hypertrophy, Right Ventricular MH - Hypoxia/*pathology MH - Lung/blood supply/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/cytology/metabolism MH - PTEN Phosphohydrolase/biosynthesis MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/*genetics MH - Pulmonary Artery/pathology MH - RNA Interference MH - RNA, Small Interfering MH - TOR Serine-Threonine Kinases/genetics MH - Tamoxifen/pharmacology MH - *Vascular Remodeling MH - Vascular Resistance PMC - PMC4338938 OTO - NOTNLM OT - Akt/mammalian target of rapamycin signaling OT - hypoxia OT - pulmonary vascular remodeling OT - smooth muscle cell proliferation EDAT- 2014/11/25 06:00 MHDA- 2015/04/22 06:00 PMCR- 2016/01/15 CRDT- 2014/11/23 06:00 PHST- 2014/11/23 06:00 [entrez] PHST- 2014/11/25 06:00 [pubmed] PHST- 2015/04/22 06:00 [medline] PHST- 2016/01/15 00:00 [pmc-release] AID - ajplung.00242.2014 [pii] AID - L-00242-2014 [pii] AID - 10.1152/ajplung.00242.2014 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L208-20. doi: 10.1152/ajplung.00242.2014. Epub 2014 Nov 21.