title: Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is associated with mutations of bone morphogenetic protein receptor 2 (BMPR2), and BMPR2 expression decreases with the development of experimental PAH. Decreased BMPR2 expression and impaired intracellular BMP signaling in pulmonary artery (PA) smooth muscle cells (PASMC) suppresses apoptosis and promotes proliferation, thereby contributing to the pathogenesis of PAH. We hypothesized that overexpression of BMPR2 in resistance PAs would ameliorate established monocrotaline PAH. Human BMPR2 was inserted into a serotype 5 adenovirus with a green fluorescent protein (GFP) reporter. Dose-dependent transgene expression was confirmed in PASMC using fluorescence microscopy, quantitative RT-PCR, and immunoblots. PAH was induced by injecting Sprague-Dawley rats with monocrotaline (60 mg/kg ip) or saline. On day 14, post-monocrotaline (MCT) rats received 5 x 10(9) plaque-forming units of either Ad-human BMPR2 (Ad-hBMPR2) or Ad-GFP. Transgene expression was confirmed by fluorescence microscopy, quantitative RT-PCR of whole lung samples, and laser-capture microdissected resistance PAs. Invasive hemodynamic and echocardiographic end points of pulmonary hypertension were assessed on day 24. Endogenous BMPR2 mRNA levels were greatest in resistance PAs, and expression declined with MCT PAH. Despite robust hBMPR2 expression in all lung lobes and within resistance PAs of treated rats, hBMPR2 did not lower mean PA pressure, pulmonary vascular resistance index, right ventricular hypertrophy, or remodeling of resistance PAs. Nebulized intratracheal adenoviral gene therapy with hBMPR2 reliably distributed hBMPR2 to resistance PAs but did not ameliorate PAH. Depressed BMPR2 expression may be a marker of PAH but is not central to the pathogenesis of this model of PAH.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2B7.
authors.forename: M Sean
authors.initials: MS
authors.lastname: McMurtry
authors.forename: Rohit
authors.initials: R
authors.lastname: Moudgil
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonnet
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D001794:Blood Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis* / Q000235:genetics; D002302:Cardiac Output; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000503:physiopathology* / Q000628:therapy; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000235:genetics
chemical_list: D016686:Monocrotaline; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II