PuSH - Publikationsserver des Helmholtz Zentrums München: Riociguat attenuates left ventricular proteome and microRNA profile changes after experimental aortic stenosis in mice.

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Benkner, A.* ; Rüdebusch, J.* ; Nath, N.* ; Hammer, E.* ; Grube, K.* ; Gross, S.* ; Dhople, V.M.* ; Eckstein, G. ; Meitinger, T. ; Kaderali, L.* ; Völker, U.* ; Fielitz, J.* ; Felix, S.B.*

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

Br. J. Pharmacol. 179, 4575-4592 (2022)

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BACKGROUND AND PURPOSE: Development and progression of heart failure (HF) involve endothelial and myocardial dysfunction as well as a dysregulation of the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate (NO-sGC-cGMP) signalling pathway. Recently, we reported that the sGC stimulator riociguat (RIO) has beneficial effects on cardiac remodelling and progression of HF in response to chronic pressure overload. Here, we examined if these favourable RIO effects are 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 RIO or vehicle for five weeks, starting three weeks post-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 (LV). KEY RESULTS: TAC-induced changes of the LV proteome were significantly reduced by RIO treatment. Bioinformatics analyses revealed that RIO improved TAC-induced cardiovascular disease related pathways, metabolism and energy production, e.g. reversed alterations in the levels of myosin heavy chain 7 (MYH7), cardiac phospholamban (PLN), and ankyrin repeat domain-containing protein 1 (ANKRD1). RIO also attenuated TAC-induced changes of microRNA levels in the LV. CONCLUSION AND IMPLICATIONS: The sGC stimulator RIO has beneficial effects on cardiac structure and function during pressure overload, which is accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of RIO as a novel HF therapeutic.

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