Behringer, Arnica, Trappiel, Manuela, Berghausen, Eva Maria, ten Freyhaus, Henrik, Wellnhofer, Ernst, Odenthal, Margarete, Blaschke, Florian, Er, Fikret, Gassanov, Natig, Rosenkranz, Stephan, Baldus, Stephan, Kappert, Kai ORCID: 0000-0001-6976-0428 and Caglayan, Evren (2016). Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension. Naunyn-Schmiedebergs Arch. Pharmacol., 389 (4). S. 369 - 380. NEW YORK: SPRINGER. ISSN 1432-1912

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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-gamma (PPAR gamma) 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 PPAR gamma might be a promising treatment option in PAH.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Behringer, ArnicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trappiel, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berghausen, Eva MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ten Freyhaus, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wellnhofer, ErnstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaschke, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Er, FikretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gassanov, NatigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenkranz, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kappert, KaiUNSPECIFIEDorcid.org/0000-0001-6976-0428UNSPECIFIED
Caglayan, EvrenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-280225
DOI: 10.1007/s00210-015-1205-3
Journal or Publication Title: Naunyn-Schmiedebergs Arch. Pharmacol.
Volume: 389
Number: 4
Page Range: S. 369 - 380
Date: 2016
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-1912
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIVATED-RECEPTOR-GAMMA; PPAR-GAMMA; INHIBITS OSTEOPONTIN; INSULIN-RESISTANCE; METABOLIC SYNDROME; GENE-EXPRESSION; PATHOGENESIS; RATS; PROLIFERATION; RELAXATIONMultiple languages
Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28022

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