Involvement of Gax gene in hypoxia-induced pulmonary hypertension, proliferation, and apoptosis of arterial smooth muscle cells.
Hypoxia down-regulates the expression of the growth arrest-specific homeobox (Gax) in pulmonary arterial smooth muscle cells (PASMCs), resulting in increased cell proliferation and decreased apoptosis, but the mechanism for this response remains unclear. The present study investigated the role of Gax in the development of hypoxia-induced pulmonary hypertension (PH). We found that hypoxia suppressed the expression of endogenous Gax in rats, but not in those pretreated intratracheally with a Gax construct (Ad-Gax). Hypoxic rats pretreated with Ad-Gax were resistant to hypoxia-induced PH, right ventricular hypertrophy, increased wall thickness, and the muscularization of pulmonary arterioles. Hypoxia-induced PASMC proliferation and suppression of Gax expression were blocked by the Mitogen-activated protein kinase (MEK) inhibitor U0126. The PASMCs with Ad-Gax transfection exhibited hyperexpression of the Bcl-2-associated X protein (Bax) and hypoexpression of B-cell lymphoma 2 (Bcl-2), leading to cell apoptosis. Thus, our data indicate that the enhanced expression of Gax inhibits hypoxia-induced PASMC proliferation, probably via the extracellular-signal-regulated kinase (ERK) 1/2 pathway, and induces the apoptosis of hypoxic PASMCs via the Bcl-2/Bax pathway. Gax may be a potential new therapeutic target for pulmonary hypertension.
Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, No.180 Fenglin Road, Shanghai, P.R. China.
Shijin
S
Xia
Xiantao
X
Tai
Yaoli
Y
Wang
Xiaojing
X
An
Guisheng
G
Qian
Jingcheng
J
Dong
Xun
X
Wang
Baokang
B
Sha
Diane
D
Wang
Padma
P
Murthi
Bill
B
Kalionis
Xiangdong
X
Wang
Chunxue
C
Bai
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D018398:Homeodomain Proteins; C081336:Meox2 protein, rat; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3