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Rüdebusch, J.* ; Benkner, A.* ; Nath, N.* ; Fleuch, L.* ; Kaderali, L.* ; Grube, K.* ; Klingel, K.* ; Eckstein, G.N. ; Meitinger, T. ; Fielitz, J.* ; Felix, S.B.*

Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling.

Br. J. Pharmacol., DOI: 10.1111/bph.15333 (2020)
Verlagsversion Forschungsdaten DOI PMC
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Background and Purpose: Heart failure is associated with an impaired NO–soluble guanylyl cyclase (sGC)–cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload. Experimental Approach: Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies. Key Results: Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts. Conclusion and Implications: Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cgmp Signalling ; Heart Failure ; Riociguat ; Rna Sequencing ; Soluble Gc ; Tac; Cyclic Guanosine-monophosphate; Pulmonary-hypertension; Double-blind; Fibrosis; Pharmacology; Hypertrophy; Guidelines; Cinaciguat; Activator; Design
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Zeitschrift British Journal of Pharmacology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
Förderungen Deutsches Zentrum für Herz-Kreislaufforschung
DOI 10.1111/bph.15333
WOS ID WOS:000603135900001
Scopus ID 85098154482
PubMed ID 33247945
Erfassungsdatum 2021-02-04
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