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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)
Publ. Version/Full Text Research data 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cgmp Signalling ; Heart Failure ; Riociguat ; Rna Sequencing ; Soluble Gc ; Tac; Cyclic Guanosine-monophosphate; Pulmonary-hypertension; Double-blind; Fibrosis; Pharmacology; Hypertrophy; Guidelines; Cinaciguat; Activator; Design
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Journal British Journal of Pharmacology
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Grants Deutsches Zentrum für Herz-Kreislaufforschung