title: A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension.
abstract: Plexiform lesions (PLs), the hallmark of plexogenic pulmonary arterial hypertension (PAH), contain phenotypically altered, proliferative endothelial cells (ECs). The molecular mechanism that contributes to EC proliferation and formation of PLs is poorly understood. We now show that a decrease in intersectin-1s (ITSN-1s) expression due to granzyme B (GrB) cleavage during inflammation associated with PAH and the high p38/Erk1/2(MAPK) activity ratio caused by the GrB/ITSN cleavage products lead to EC proliferation and selection of a proliferative/plexiform EC phenotype. We used human pulmonary artery ECs of PAH subjects (EC(PAH)), paraffin-embedded and frozen human lung tissue, and animal models of PAH in conjunction with microscopy imaging, biochemical, and molecular biology approaches to demonstrate that GrB cleaves ITSN-1s, a prosurvival protein of lung ECs, and generates two biologically active fragments, an N-terminal fragment (GrB-EH(ITSN)) with EC proliferative potential and a C-terminal product with dominant negative effects on Ras/Erk1/2. The proliferative potential of GrB-EH(ITSN) is mediated via sustained phosphorylation of p38(MAPK) and Elk-1 transcription factor and abolished by chemical inhibition of p38(MAPK). Moreover, lung tissue of PAH animal models and human specimens and EC(PAH) express lower levels of ITSN-1s compared with controls and the GrB-EH(ITSN) cleavage product. Moreover, GrB immunoreactivity is associated with PLs in PAH lungs. The concurrent expression of the two cleavage products results in a high p38/Erk1/2(MAPK) activity ratio, which is critical for EC proliferation. Our findings identify a novel GrB-EH(ITSN)-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH.
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Monal
authors.initials: M
authors.lastname: Patel
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Dan
authors.initials: D
authors.lastname: Predescu
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Rajive
authors.initials: R
authors.lastname: Tandon
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bardita
authors.affiliation: Department of Pathology and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogoriler
authors.affiliation: Center for Lung Transplant, University of Chicago, Chicago, Illinois 60637.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Bhorade
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Minhua
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Suzy
authors.initials: S
authors.lastname: Comhair
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee 37240, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Ryan-Hemnes
authors.affiliation: Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois, Chicago, Illinois 60612.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois, Chicago, Illinois 60612.
authors.forename: Roberto
authors.initials: R
authors.lastname: Machado
authors.affiliation: Department of Pathology and.
authors.forename: Aliya
authors.initials: A
authors.lastname: Husain
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Serpil
authors.initials: S
authors.lastname: Erzurum
authors.affiliation: From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612,. Electronic address: sanda_predescu@rush.edu.
authors.forename: Sanda
authors.initials: S
authors.lastname: Predescu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; C485568:ITSN1 protein, human; D050807:ets-Domain Protein Elk-1; C115919:intersectin 1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse
keywords: Endothelium; Proliferation; Pulmonary Hypertension; Vascular Biology; p38 MAPK
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