Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2015 Jan 15;308(2):L208-20
Date
11/25/2014Pubmed ID
25416384Pubmed Central ID
PMC4338938DOI
10.1152/ajplung.00242.2014Scopus ID
2-s2.0-84921299135 (requires institutional sign-in at Scopus site) 81 CitationsAbstract
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.
Author List
Tang H, Chen J, Fraidenburg DR, Song S, Sysol JR, Drennan AR, Offermanns S, Ye RD, Bonini MG, Minshall RD, Garcia JG, Machado RF, Makino A, Yuan JXMESH terms used to index this publication - Major topics in bold
AnimalsBlood Pressure
Cell Movement
Cell Proliferation
Humans
Hypertension, Pulmonary
Hypertrophy, Right Ventricular
Hypoxia
Lung
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
PTEN Phosphohydrolase
Phosphorylation
Proto-Oncogene Proteins c-akt
Pulmonary Artery
RNA Interference
RNA, Small Interfering
TOR Serine-Threonine Kinases
Tamoxifen
Vascular Remodeling
Vascular Resistance
