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

Haiyang Tang, Jiwang Chen, Dustin R. Fraidenburg, Shanshan Song, Justin R. Sysol, Abigail R. Drennan, Stefan Offermanns, Richard D. Ye, Marcelo G. Bonini, Richard D. Minshall, Joe GN Garcia, Roberto F. Machado, Ayako Makino, Jason Yuan

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L208-L220
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number2
DOIs
StatePublished - Jan 15 2015

Fingerprint

Pulmonary Hypertension
Lung
Protein Isoforms
Sirolimus
Smooth Muscle Myocytes
Cell Movement
Cell Proliferation
Right Ventricular Hypertrophy
Chromosomes, Human, Pair 10
Ventricular Pressure
Phosphoric Monoester Hydrolases
Vascular Resistance
Arterial Pressure
Hypoxia
Blood Pressure
Vascular Remodeling

Keywords

  • Akt/mammalian target of rapamycin signaling
  • Hypoxia
  • Pulmonary vascular remodeling
  • Smooth muscle cell proliferation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. / Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R.; Song, Shanshan; Sysol, Justin R.; Drennan, Abigail R.; Offermanns, Stefan; Ye, Richard D.; Bonini, Marcelo G.; Minshall, Richard D.; Garcia, Joe GN; Machado, Roberto F.; Makino, Ayako; Yuan, Jason.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 308, No. 2, 15.01.2015, p. L208-L220.

Research output: Contribution to journalArticle

Tang, 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, J 2015, 'Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 308, no. 2, pp. L208-L220. https://doi.org/10.1152/ajplung.00242.2014
Tang, Haiyang ; Chen, Jiwang ; Fraidenburg, Dustin R. ; Song, Shanshan ; Sysol, Justin R. ; Drennan, Abigail R. ; Offermanns, Stefan ; Ye, Richard D. ; Bonini, Marcelo G. ; Minshall, Richard D. ; Garcia, Joe GN ; Machado, Roberto F. ; Makino, Ayako ; Yuan, Jason. / Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015 ; Vol. 308, No. 2. pp. L208-L220.
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abstract = "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.",
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AU - Chen, Jiwang

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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 GN

AU - Machado, Roberto F.

AU - Makino, Ayako

AU - Yuan, Jason

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