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

Tang H1, Chen J2, Fraidenburg DR2, Song S1, Sysol JR3, Drennan AR2, Offermanns S4, Ye RD5, Bonini MG5, Minshall RD5, Garcia JG6, Machado RF2,Makino A7, Yuan JX8.

Am J Physiol Lung Cell Mol Physiol. 2015 ;308(2):L208-20.

 

1Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;

2Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois;

3Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.

4Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

5Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and.

6Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona;

7Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona;

8Department of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona; Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona; Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and [email protected]

 

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.

Copyright © 2015 the American Physiological Society.

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