Activation of the phosphatidylinositol 3-kinase/Akt pathway is involved in lipocalin-2-promoted human pulmonary artery smooth muscle cell proliferation.
Over-activated PI3K/Akt signaling, a pathway strongly related to cancer survival and proliferation, has been reported recently to be involved in pulmonary artery smooth muscle cell apoptosis and proliferation in pulmonary hypertension (PH). In this study, we observed greatly increased lipocalin-2 (Lcn2) expression accompanied with over-activated PI3K/Akt signaling in a standard rat model of PH induced by monocrotaline. In view of the close relationship between Lcn2 and PI3K/Akt pathway, we hypothesized that the up-regulated Lcn2 might be a trigger of over-activated PI3K/Akt signaling in PH. Our results showed that Lcn2 significantly activated the PI3K/Akt pathway (determined by augmented Akt phosphorylation and up-regulated Mdm2) and significantly promoted proliferation (assessed by Ki67 staining) in cultured human pulmonary artery smooth muscle cells. Furthermore, we demonstrated that inhibition of Akt phosphorylation (LY294002) abrogated the Lcn2-promoted proliferation in cultured human pulmonary artery smooth muscle cells. In conclusion, Lcn2 significantly promoted human pulmonary artery smooth muscle cell proliferation by activating PI3K/Akt pathway. Further study on the role and mechanism of Lcn2 will help explore novel therapeutic strategies based on attenuating over-activated PI3K/Akt signaling in PH.
Key Laboratory of Major Diseases in Children by Ministry of Education, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.|Laboratory of Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.|State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Guoliang
G
Wang
Key Laboratory of Major Diseases in Children by Ministry of Education, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
Ning
N
Ma
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Liukun
L
Meng
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yingjie
Y
Wei
Key Laboratory of Major Diseases in Children by Ministry of Education, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China. jingang_gui@163.com.|Laboratory of Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China. jingang_gui@163.com.
Jingang
J
Gui
D000209:Acute-Phase Proteins / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D066253:Vascular Remodeling / Q000187:drug effects*
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016686:Monocrotaline; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
Akt; Lipocalin-2 (Lcn2); Phosphorylation; Proliferation; Pulmonary hypertension (PH)