TY - JOUR
T1 - Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension
AU - Tang, Haiyang
AU - Chen, Jiwang
AU - Fraidenburg, Dustin R.
AU - Song, Shanshan
AU - Sysol, Justin R.
AU - Drennan, Abigail R.
AU - Offermanns, Stefan
AU - Ye, Richard D.
AU - Bonini, Marcelo G.
AU - Minshall, Richard D.
AU - Garcia, Joe G.N.
AU - Machado, Roberto F.
AU - Makino, Ayako
AU - Yuan, Jason X.J.
N1 - Publisher Copyright:
© 2015 the American Physiological Society.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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.
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.
KW - Akt/mammalian target of rapamycin signaling
KW - Hypoxia
KW - Pulmonary vascular remodeling
KW - Smooth muscle cell proliferation
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U2 - 10.1152/ajplung.00242.2014
DO - 10.1152/ajplung.00242.2014
M3 - Article
C2 - 25416384
AN - SCOPUS:84921299135
VL - 308
SP - L208-L220
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 2
ER -