Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension

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• 作者：Arnica Behringer ; Manuela Trappiel…
• 关键词：Pulmonary hypertension ; Rat ; PPAR ; Monocrotaline ; Right ventricle
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：389
• 期：4
• 页码：369-379
• 全文大小：1,480 KB
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• 作者单位：Arnica Behringer (1)
  Manuela Trappiel (2)
  Eva Maria Berghausen (1)
  Henrik ten Freyhaus (1)
  Ernst Wellnhofer (3)
  Margarete Odenthal (5)
  Florian Blaschke (4)
  Fikret Er (6)
  Natig Gassanov (6)
  Stephan Rosenkranz (1)
  Stephan Baldus (1)
  Kai Kappert (2)
  Evren Caglayan (1)
  
  1. Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany
  2. Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry; Center for Cardiovascular Research (CCR), Charité–University Medicine Berlin, Berlin, Germany
  3. Department of Cardiology, German Heart Center Berlin, Berlin, Germany
  5. Department of Pathology, University of Cologne, Cologne, Germany
  4. Department of Cardiology, Charité–University Medicine Berlin, Berlin, Germany
  6. Klinikum Gütersloh gGmbH, Gütersloh, Germany
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

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.