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Int. J. Mol. Sci. 2017, 18(8), 1609; doi:10.3390/ijms18081609

Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension

1
Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf 40225, Germany
2
Department of Internal Medicine I, Jena University Hospital, Jena 07747, Germany
3
Department of Angiology, Cardiovascular Center Bad Bevensen, Bad Bevensen 29549, Germany
4
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 171 76, Sweden
5
Klinik für Innere Medizin I, Ilm-Kreis-Kliniken Arnstadt, Arnstadt 99310, Germany
6
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
7
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena 07745, Germany
8
Department of Cardiology, Charité – Universitätsmedizin Berlin, Berlin 12203, Germany
9
Institute of Pathology, Jena University Hospital, Jena 07743, Germany
*
Author to whom correspondence should be addressed.
Received: 4 June 2017 / Revised: 13 July 2017 / Accepted: 20 July 2017 / Published: 25 July 2017
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague–Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH. View Full-Text
Keywords: pulmonary hypertension; monocrotaline rat model; arginase; isoforms; inhibition pulmonary hypertension; monocrotaline rat model; arginase; isoforms; inhibition
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MDPI and ACS Style

Jung, C.; Grün, K.; Betge, S.; Pernow, J.; Kelm, M.; Muessig, J.; Masyuk, M.; Kuethe, F.; Ndongson-Dongmo, B.; Bauer, R.; Lauten, A.; Schulze, P.C.; Berndt, A.; Franz, M. Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension. Int. J. Mol. Sci. 2017, 18, 1609.

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