title: Endothelial-like progenitor cells engineered to produce prostacyclin rescue monocrotaline-induced pulmonary arterial hypertension and provide right ventricle benefits.
abstract: BACKGROUND
  Intravenous prostacyclin is approved for treating pulmonary arterial hypertension (PAH), but it has a short half-life and must be delivered systemically via an indwelling intravenous catheter. We hypothesize that localized jugular vein delivery of prostacyclin-producing cells may provide sustained therapeutic effects without the limitations of systemic delivery.
  
  
  RESULTS
  We generated a vector expressing a human cyclooxygenase isoform 1 and prostacyclin synthase fusion protein that produces prostacyclin from arachidonic acid. Endothelial-like progenitor cells (ELPCs) were transfected with the cyclooxygenase isoform 1-prostacyclin synthase plasmid and labeled with lentivirus expressing nuclear-localized red fluorescent protein (nuRFP). The engineered ELPCs (expressing cyclooxygenase isoform 1-prostacyclin synthase and nuRFP) were tested in rats with monocrotaline (MCT)-induced PAH. In PAH prevention studies, treatment with engineered ELPCs or control ELPCs (expressing nuRFP alone) attenuated MCT-induced right ventricular systolic pressure increase, right ventricular hypertrophy, and pulmonary vessel wall thickening. Engineered ELPCs were more effective than control ELPCs in all variables evaluated. In PAH reversal studies, engineered ELPCs or control ELPCs increased the survival rate of rats with established PAH and decreased right ventricular hypertrophy. Engineered ELPCs provided a survival benefit 2 weeks earlier than did control ELPCs. Microarray-based gene ontology analysis of the right ventricle revealed that a number of MCT-altered genes and neurotransmitter pathways (dopamine, serotonin, and γ-aminobutyric acid) were restored after ELPC-based prostacyclin gene therapy.
  
  
  CONCLUSIONS
  Cyclooxygenase isoform 1-prostacyclin synthase-expressing ELPCs reversed MCT-induced PAH. A single jugular vein injection offered survival benefits for at least 4 weeks and may provide a promising option for PAH patients.
authors.affiliation: Department of Molecular Cardiology, Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Vanderslice
authors.forename: Shui-Ping
authors.initials: SP
authors.lastname: So
authors.forename: Ke-He
authors.initials: KH
authors.lastname: Ruan
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: Richard A F
authors.initials: RA
authors.lastname: Dixon
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000637:transplantation*; D011464:Epoprostenol / Q000235:genetics* / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000378:metabolism / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D007262:Infusions, Intravenous; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects*; D051381:Rats; D011916:Rats, Inbred F344; D033581:Stem Cell Transplantation; D015996:Survival Rate; D023822:Tissue Engineering; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase
keywords: bone marrow cells; epoprostenol; hypertrophy; microarray analysis; neurotransmitter agents