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

作者：Haiyang Tang, Jiwang Chen, Dustin R. Fraidenburg, Shanshan Song, Justin R. Sysol, Abigail Drennan, Stefan Offermanns, Richard D. Ye, Marcelo G. Bonini, Richard D. Minshall, Joe G. N. Garcia, Roberto F. Machado, Ayako Makino, Jason X.‐J. Yuan · 发表于：American Journal of Physiology-Lung Cellular and Molecular Physiology · 年份：2014 · DOI：10.1152/ajplung.00242.2014 · 被引用次数：99 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Pulmonary Hypertension Research and Treatments

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 uni...