title: Iloprost reverses established fibrosis in experimental right ventricular failure.
abstract: Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA jgomeza1@jhmi.edu.
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Arroyo
authors.affiliation: Dept of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Aamer A
authors.initials: AA
authors.lastname: Syed
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Van Tassell
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.affiliation: Division of Respiratory Diseases, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: Dept of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Bogaard
authors.affiliation: Dept of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Byron
authors.affiliation: Victoria Johnson Center for Lung Obstructive Disease Research, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004452:Echocardiography; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000139:chemically induced; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy*; D000860:Hypoxia / Q000503:physiopathology; D016285:Iloprost / Q000627:therapeutic use*; D007211:Indoles; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D010805:Physical Conditioning, Animal; D011347:Procollagen / Q000378:metabolism; D011758:Pyrroles; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use; D016278:Ventricular Function, Right
chemical_list: D007211:Indoles; D011347:Procollagen; D011758:Pyrroles; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014665:Vasodilator Agents; C116890:Semaxinib; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D016285:Iloprost