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

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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-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.

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Acknowledgments

This study was supported by the Marga und Walter Boll-Stiftung (210-04-10) to K.K. and E.C. M.T. is supported by a PhD scholarship of the Charité-Nachwuchskommission.

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    Authors and Affiliations

    1. Department of Internal Medicine III; Heart Center, University of Cologne, Cologne, Germany

      Arnica Behringer, Eva Maria Berghausen, Henrik ten Freyhaus, Stephan Rosenkranz, Stephan Baldus & Evren Caglayan

    2. Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry; Center for Cardiovascular Research (CCR), Charité–University Medicine Berlin, Berlin, Germany

      Manuela Trappiel & Kai Kappert

    3. Department of Cardiology, German Heart Center Berlin, Berlin, Germany

      Ernst Wellnhofer

    4. Department of Cardiology, Charité–University Medicine Berlin, Berlin, Germany

      Florian Blaschke

    5. Department of Pathology, University of Cologne, Cologne, Germany

      Margarete Odenthal

    6. Klinikum Gütersloh gGmbH, Gütersloh, Germany

      Fikret Er & Natig Gassanov

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    1. Arnica Behringer
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    Correspondence to Evren Caglayan.

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    All animal care and experiments were performed in accordance with the German Laws for Animal Protections and were approved by the local animal care committee.

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    Arnica Behringer, Manuela Trappiel, Kai Kappert and Evren Caglayan contributed equally to this work.

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    Behringer, A., Trappiel, M., Berghausen, E.M. et al. Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension. Naunyn-Schmiedeberg's Arch Pharmacol 389, 369–379 (2016). https://doi.org/10.1007/s00210-015-1205-3

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    • DOI: https://doi.org/10.1007/s00210-015-1205-3

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