title: Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed.
abstract: Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EHITSN), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EHITSNvia liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative α-smooth muscle actin-positive cells in the lungs of ITSN-deficient mice, transduced with the EHITSNrelative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiform-like lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38MAPK-dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH.
authors.affiliation: Department of Pharmacology & Internal Medicine, Division of Pulmonary and Critical Care, Rush University Medical Center, Chicago, Illinois; Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Monal
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Pharmacology & Internal Medicine, Division of Pulmonary and Critical Care, Rush University Medical Center, Chicago, Illinois; Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Dan
authors.initials: D
authors.lastname: Predescu
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bardita
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Jeganathan
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Pritchard
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiBartolo
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Roberto
authors.initials: R
authors.lastname: Machado
authors.affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, Illinois. Electronic address: sanda_predescu@rush.edu.
authors.forename: Sanda
authors.initials: S
authors.lastname: Predescu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology; D006984:Hypertrophy / Q000473:pathology / Q000503:physiopathology; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology* / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000378:metabolism; D013599:Systole; D014161:Transduction, Genetic; D066253:Vascular Remodeling; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008055:Lipids; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D050807:ets-Domain Protein Elk-1; C115919:intersectin 1; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases