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Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension
Tang H.1; Chen J.2; Fraidenburg D.R.2; Song S.1; Sysol J.R.2; Drennan A.R.2; Offermanns S.3; Ye R.D.2; Bonini M.G.2; Minshall R.D.2; Garcia J.G.N.1; Machado R.F.2; Makino A.1; Yuan J.X.-J.1
2015
Source PublicationAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
ISSN15221504 10400605
Volume308Issue:2Pages:L208-L220
AbstractPulmonary 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% O). 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.
KeywordAkt/mammalian target of rapamycin signaling Hypoxia Pulmonary vascular remodeling Smooth muscle cell proliferation
DOI10.1152/ajplung.00242.2014
URLView the original
Language英語
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被引频次[WOS]:33   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题University of Macau
Affiliation1.University of Arizona College of Medicine - Tucson
2.University of Illinois at Chicago
3.Max Planck Institut fur Herz- und Lungenforschung
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Tang H.,Chen J.,Fraidenburg D.R.,et al. Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension[J]. American Journal of Physiology - Lung Cellular and Molecular Physiology,2015,308(2):L208-L220.
APA Tang H..,Chen J..,Fraidenburg D.R..,Song S..,Sysol J.R..,...&Yuan J.X.-J..(2015).Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension.American Journal of Physiology - Lung Cellular and Molecular Physiology,308(2),L208-L220.
MLA Tang H.,et al."Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension".American Journal of Physiology - Lung Cellular and Molecular Physiology 308.2(2015):L208-L220.
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