Suppression of Akt1 phosphorylation by adenoviral transfer of the PTEN gene inhibits hypoxia-induced proliferation of rat pulmonary arterial smooth muscle cells.
Recent findings identify the role of proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. Phosphoinositide 3 kinase (PI3K) and serine/threonine kinase (Akt) proteins are expressed in vascular smooth muscle cells. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been identified as a negative regulator of cytokine signaling that inhibits the PI3K-Akt pathway. However, little is known about the role of PTEN/Akt signaling in hypoxia-associated vascular remodeling. In this study, we found that hypoxia-induced the expression of Akt1 mRNA and phosphorylated protein by at least twofold in rat PASMCs. Phospho-PTEN significantly decreased in the nuclei of PASMCs after hypoxic stimulation. After forcing over-expression of PTEN by adenovirus-mediated PTEN (Ad-PTEN) transfection, the expression of phospho-Akt1 was significantly suppressed in PASMCs at all time-points measured. Additionally, we showed here that hypoxia increased proliferation of PASMCs by nearly twofold and over-expression of PTEN significantly inhibited hypoxia-induced PASMCs proliferation. These findings suggest that phospho-PTEN loss in the nuclei of PASMCs under hypoxic conditions may be the major cause of aberrant activation of Akt1 and may, therefore, play an important role in hypoxia-associated pulmonary arterial remodeling. Finally, the fact that transfection with Ad-PTEN inhibits the phosphorylation of Akt1 in PASMCs suggests a potential therapeutic effect on hypoxia-associated pulmonary arterial remodeling.
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Chunxia
C
Luo
Bin
B
Yi
Li
L
Bai
Yongzhi
Y
Xia
Guansong
G
Wang
Guisheng
G
Qian
Hua
H
Feng
D000256:Adenoviridae; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D018014:Gene Transfer Techniques; D000860:Hypoxia / Q000235:genetics / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D013489:Suppression, Genetic
D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase