title: Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Arnica
authors.initials: A
authors.lastname: Behringer
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry; Center for Cardiovascular Research (CCR), Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Trappiel
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Berghausen
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ten Freyhaus
authors.affiliation: Department of Cardiology, German Heart Center Berlin, Berlin, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wellnhofer
authors.affiliation: Department of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.affiliation: Department of Cardiology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Blaschke
authors.affiliation: Klinikum Gütersloh gGmbH, Gütersloh, Germany.
authors.forename: Fikret
authors.initials: F
authors.lastname: Er
authors.affiliation: Klinikum Gütersloh gGmbH, Gütersloh, Germany.
authors.forename: Natig
authors.initials: N
authors.lastname: Gassanov
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry; Center for Cardiovascular Research (CCR), Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.affiliation: Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany. evren.caglayan@uk-koeln.de.
authors.forename: Evren
authors.initials: E
authors.lastname: Caglayan
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*; D066253:Vascular Remodeling / Q000187:drug effects*; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002317:Cardiovascular Agents; D047495:PPAR gamma; C506897:Spp1 protein, rat; D045162:Thiazolidinediones; D053495:Osteopontin; D020097:Natriuretic Peptide, Brain; D016686:Monocrotaline; D000077205:Pioglitazone
keywords: Monocrotaline; PPAR; Pulmonary hypertension; Rat; Right ventricle