Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways.
Transforming growth factor-beta1 (TGFβ1) and Phosphatase and Tensin homolog deleted on chromosome ten (PTEN) are involved in the regulation of proliferation, differentiation, migration and apoptosis of various cell types. In previous studies, we have shown that TGFβ1 and PTEN play an important role in the progression of pulmonary vascular remodeling induced by pulmonary artery smooth muscle cells (PASMCs). However, the mechanisms involved in the activation of PASMCs between TGFβ1 and PTEN pathways remain unknown. We found that pulmonary vascular walls in hypoxic pulmonary arterial hypertension (PAH) rats were thicker than the vessels from normal rats in vivo. Substantially higher levels of TGFβ1 and significant loss of PTEN expression were observed in the lungs of PAH rats when compared with normoxia. Meanwhile, AKT, a downstream proliferative signaling protein of the PTEN antagonist PI3K, was markedly activated in the lungs of PAH rats. In vitro studies using PASMCs showed that TGFβ1 increased cell proliferation in PTEN-dependent manner. Moreover, we found that TGFβ1 enhanced cell survival, up-regulated the expression of Bcl-2 and procaspase-3, decreased the number of TUNEL-positive cells and caspase-3 expression in PASMCs under serum-deprived (SD) condition via PI3K/AKT pathway. The results further establish that TGFβ1 promoted PAH by decreasing PTEN expression and increasing PI3K/AKT activation in the lung. In conclusion, TGFβ1 mediated PTEN inactivation and resistance to apoptosis seems to be key mediators of lung vascular remodeling associated with PAH. These findings further clarify molecular mechanisms that support targeting PTEN/AKT signaling pathway to attenuate pathogenic derangements in PAH.
Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222002, PR China.
Yun
Y
Liu
Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, PR China.
Yonggang
Y
Cao
Overseas Education College, Nanjing Tech University, 30 Puzhu South Road, Nanjing 211816, PR China.
Shuyang
S
Sun
Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222002, PR China.
Jinquan
J
Zhu
Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222002, PR China.
Shan
S
Gao
Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222002, PR China.
Jie
J
Pang
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing 163319, PR China; Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin, PR China. Electronic address: dalingz@yahoo.com.
Daling
D
Zhu
Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222002, PR China. Electronic address: sunzx715@163.com.
Zengxian
Z
Sun
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D053938:DNA Fragmentation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000150:complications; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D004792:Enzyme Precursors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053773:Transforming Growth Factor beta1; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D053148:Caspase 3; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
Apoptosis; PTEN/AKT; Proliferation; Pulmonary arterial hypertension; Transforming growth factor-beta1