Riociguat attenuates the changes in left ventricular proteome and microRNA profile after experimental aortic stenosis in mice

Abstract

Background and Purpose Development and progression of heart failure involve endothelial and myocardial dysfunction as well as a dysregulation of the NO‐sGC‐cGMP signalling pathway. Recently, we reported that the sGC stimulator riociguat has beneficial effects on cardiac remodelling and progression of heart failure in response to chronic pressure overload. Here, we examined if these beneficial effects of riociguat were also reflected in alterations of the myocardial proteome and microRNA profiles. Experimental Approach Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham‐operated mice served as controls. TAC and sham animals were randomised and treated with either riociguat or vehicle for 5 weeks, starting 3 weeks after surgery, when cardiac hypertrophy was established. Afterwards, we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LVs). Key Results TAC‐induced changes of the LV proteome were significantly reduced by treatment with riociguat. Bioinformatics analyses revealed that riociguat improved TAC‐induced cardiovascular disease‐related pathways, metabolism and energy production, for example, reversed alterations in the levels of myosin heavy chain 7, cardiac phospholamban and ankyrin repeat domain‐containing protein 1. Riociguat also attenuated TAC‐induced changes of microRNA levels in the LV. Conclusion and Implications The sGC stimulator riociguat exerted beneficial effects on cardiac structure and function during pressure overload, which was accompanied by a reversal of TAC‐induced changes of the cardiac proteome and microRNA profile. Our data support the potential of riociguat as a novel therapeutic agent for heart failure.

Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases

“…Riociguat also attenuates TAC-induced changes in left ventricular microRNA levels. This suggests that riociguat has beneficial effects on cardiac structure and function during stress overload, supporting the potential use of riociguat as a novel treatment for HF ( Benkner et al, 2022 ).…”

Protective Effect of Shengmaiyin in Myocardial Hypertrophy-Induced Rats: A Genomic Analysis by 16S rDNA

“…Clinically, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, β -receptor blockers, and calcium channel blockers are mainly used for the treatment of myocardial hypertrophy [ 5 – 7 ]. However, while these treatments can delay the occurrence and development of myocardial hypertrophy and fibrosis to a certain extent, they cannot significantly delay the development of heart failure [ 8 ]. Therefore, it is of great significance and value to identify drugs that inhibit myocardial cell hypertrophy and myocardial fibrosis to prevent and treat myocardial hypertrophy.…”