Influence of the Soluble Guanylate Cyclase Stimulator Riociguat on Myocardial Function and Proteome after Experimental Aortic Stenosis in Mice
Authors: Benkner Alexander , Ruedebusch Julia , Klingel Karin , Hammer Elke , Witt Eric , Dhople Vishnu Mukund , Doerr Marcus , Felix Stephan , Grube Karina 
Published: June 2021

Background

The development and progression of heart failure (HF) involves endothelial and myocardial dysfunction as well as a dysregulation of different signaling pathways, including the nitric oxide – soluble guanylate cyclase – cyclic guanosine monophosphate signaling (NO‐sGC‐cGMP). Riociguat is a stimulator of sGC and could have beneficial effects in chronic HF with reduced left ventricular ejection fraction (LVEF) by preventing or even reversing the progression of hypertrophy and fibrosis.

Methods

Transverse aortic constriction (TAC) was used to simulate arterial hypertension by an increased afterload in 8 week old male C57Bl6/N mice. Animals with sham surgery were used as controls. Three weeks after TAC either Riociguat (TAC/RIO; 3 mg/kg) or placebo (TAC/P) were administered by daily gavage for 5 more weeks (n = 12 per group). Sham animals were also treated with RIO (Sham/RIO) or placebo (Sham/P) in the same drug regime (n = 12 per group). Cardiac structure and function was evaluated weekly by small animal echocardiography. Eight weeks after TAC myocardial tissue sections were stained by sirius red to determine fibrosis levels (n = 6 per group), and proteomes of the left ventricles (LV) were analyzed by mass spectrometry (n = 6 per group). Significantly altered proteins were categorized using Ingenuity Pathway Analysis (IPA).

Results

TAC decreased left ventricular systolic function over time (LVEF week 1: sham: 54.6±2.2 vs. TAC: 42.8±3.1%; week 8: sham: 53.6±3.7 vs. TAC: 20.9±4.3%, p<0.001) and increased left ventricular mass to body weight ratios (LVM/BW) (week 1: sham: 4.1±0.2 vs. TAC: 5.7±0.3 mg/g; week 8: sham: 3.8±0.1 vs. TAC: 7.7±0.7 mg/g; p<0.001), whereas in sham mice no changes occurred. This hypertrophic response and the decreased heart function of TAC mice recovered significantly after Riociguat treatment (TAC/RIO), but did not completely achieve left ventricular systolic function of healthy sham placebo treated animals (LVEF week 4: TAC/P: 27.7±5.3 vs. TAC/RIO: 37.7±3.2%; week 8: TAC/P: 20.9±4.3 vs. TAC/RIO: 43.4±6.0%, p<0.001). Riociguat did not influence cardiac function in sham mice. Sirius red staining of myocardial tissue sections revealed a trend towards more fibrosis in TAC mice, which was also detected in the proteome (Collagen↑). Reverting effects due to Riociguat treatment were seen in the histologic and also proteomic analyses (Collagen↓). Furthermore, the proteome analyses showed that alterations of proteins assigned to the IPA category “cardiovascular diseases” due to TAC were partially reverted upon drug treatment in TAC/RIO, such as Myosin‐7. This HF marker was more than tenfold higher in TAC compared to the sham group, but much less abundant in TAC/RIO. Riociguat treatment did not influence the myocardial proteome in sham mice.

Conclusion

This study revealed beneficial effects of sGC stimulation in a model of pressure overload induced HF. Riociguat treatment not only improved left ventricular systolic heart function, but also reduced the hypertrophic response due to TAC.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.