Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension.

TitleDeficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension.
Publication TypeJournal Article
Year of Publication2015
AuthorsTang H, Chen J, Fraidenburg DR, Song S, Sysol JR, Drennan AR, Offermanns S, Ye RD, Bonini MG, Minshall RD, Garcia JGN, Machado RF, Makino A, Yuan JX-J
JournalAm J Physiol Lung Cell Mol Physiol
Volume308
Issue2
PaginationL208-20
Date Published2015 Jan 15
ISSN Number1522-1504
KeywordsAnimals, Blood Pressure, Cell Movement, Cell Proliferation, Humans, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Lung, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Phosphorylation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Pulmonary Artery, RNA Interference, RNA, Small Interfering, Tamoxifen, TOR Serine-Threonine Kinases, Vascular Remodeling, Vascular Resistance
Abstract

<p>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.</p>

DOI10.1152/ajplung.00242.2014
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID25416384
PubMed Central IDPMC4338938
Grant ListHL066012 / HL / NHLBI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States
HL125208 / HL / NHLBI NIH HHS / United States
R01 HL115014 / HL / NHLBI NIH HHS / United States
HL 115014 / HL / NHLBI NIH HHS / United States
HL082547 / HL / NHLBI NIH HHS / United States
U01 HL125208 / HL / NHLBI NIH HHS / United States
R01 HL066012 / HL / NHLBI NIH HHS / United States
P01 HL060678 / HL / NHLBI NIH HHS / United States
HL098053 / HL / NHLBI NIH HHS / United States