Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.
Masri
Fares A
FA
Department of Pathobiology, Allergy and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Xu
Weiling
W
Comhair
Suzy A A
SA
Asosingh
Kewal
K
Koo
Michelle
M
Vasanji
Amit
A
Drazba
Judith
J
Anand-Apte
Bela
B
Erzurum
Serpil C
SC
D000328:Adult; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D019409:Interleukin-15 / Q000378:metabolism; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
D019409:Interleukin-15; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor