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| Item Type: | Review |
|---|---|
| Title: | Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling |
| Creators Name: | Rüdebusch, J. and Benkner, A. and Nath, N. and Fleuch, L. and Kaderali, L. and Grube, K. and Klingel, K. and Eckstein, G. and Meitinger, T. and Fielitz, J. and Felix, S.B. |
| Abstract: | BACKGROUND AND PURPOSE: Heart failure (HF) is associated with an impaired NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, and its augmentation is thought to be beneficial in HF therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat (Rio) prevents pathological cardiac remodelling and HF in response to chronic pressure overload. EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6N mice. After 3 weeks of TAC when HF was established, animals were randomized to receive either riociguat (Rio) or its solvent (Sol) 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 (LV) was analysed by RNA Sequencing. Cell culture experiments were used for mechanistically studies. KEY RESULTS: TAC resulted in a continuous decrease of LV ejection fraction (LVEF from 56.6±2.2 to 32.0±4.1%) and an increase in LV mass (LVM/BW from 3.7±0.2 to 6.1±0.3 mg/g) until week 3. Five weeks of riociguat treatment resulted in an improved LVEF (TAC+Rio 43.4±6.0% vs. TAC+Sol 20.9±4.3%; p<0.001) and a decrease in LVM/BW (5.5±0.4 mg/g vs.7.7±0.7 mg/g; p<0.001), 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, collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and HF. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts. CONCLUSION AND IMPLICATION: Stimulation of the sGC reverses TAC-induced HF and remodelling, which is associated with improved myocardial gene expression. |
| Keywords: | Heart Failure, Soluble Guanylate Cyclase, cGMP Signalling, Riociguat, TAC, RNA Sequencing, Animals, Mice |
| Source: | British Journal of Pharmacology |
| ISSN: | 0007-1188 |
| Publisher: | Wiley |
| Volume: | 179 |
| Number: | 11 |
| Page Range: | 2430-2442 |
| Date: | June 2020 |
| Official Publication: | https://doi.org/10.1111/bph.15333 |
| PubMed: | View item in PubMed |
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