Chronic Stimulation of Soluble Guanylyl Cyclase Prevents Diastolic Dysfunction by Reducing Oxidative and Metabolic Stress and Restoring Endothelial and Cardiomyocyte Function

M. Herwig (Bochum)¹, Á. Kovács (bochum)², A. B. Gevaert (Antwerp)³, M. Sieme (Bochum)⁴, S. Delalat (Bochum)⁴, S. Zhazykbayeva (Bochum)⁴, D. Kolijn (Bochum)⁴, A. J. Leloup (Antwerp)⁵, P. Fransen (Antwerp)⁶, G. Á. Fülöp (Debrecen)⁷, M. Lodí (Bochum)⁴, D. Czuriga (Debrecen)⁸, Z. F. Kisvárday (Debrecen)⁹, L. van Heerebeek (AC Amsterdam)¹⁰, P. Sandner (Wuppertal)¹¹, Z. Papp (Debrecen)⁷, S. Van Linthout (Berlin)¹², C. Tschöpe (Berlin)¹³, A. Mügge (Bochum)¹⁴, G. W. De Keulenaer (Antwerp)¹⁵, W. A. Linke (Münster)¹⁶, N. Hamdani (Bochum)^17
1Institut für Physiologie, Institut für Forschung und Lehre (IFL), Ruhr-Universität Bochum Abteilung für Zelluläre und Translationale Physiologie, Molekulare und Experimentelle Kardiologie Bochum, Deutschland; ²Abteilung für Zelluläre und Translationale Physiologie, Molekulare und Experimentelle Kardiologie, Institut für Physiologie, Institut für Forschung und Lehre (IFL), Ruhr-Universität Bochum, Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary. bochum, Deutschland; ³Department of Pharmaceutical Sciences, Laboratory of Physiopharmacology, University of Antwerp Antwerp, Belgien; ⁴Medical Faculty, Department of Cellular and Translational Physiology, Institute of Physiology, Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum Bochum, Deutschland; ⁵University of Antwerp Laboratory of Physiopharmacology Antwerp, Belgien; ⁶University of Antwerp Department of Pharmaceutical Science Antwerp, Ungarn; ⁷Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen Debrecen, Ungarn; ⁸The Royal Brompton and Harefield NHS Trust Division of Cardiology Debrecen, Ungarn; ⁹University of Debrecen Department of Anatomy Debrecen, Deutschland; ¹⁰Onze Lieve Vrouwe Gasthius Amsterdam Department of Cardiology AC Amsterdam, Niederlande; ¹¹Bayer AG Cardiovascular-Renal-Immunology Research Wuppertal, Deutschland; ¹²Charité - Universitätsmedizin Berlin BIH Center für regenerative Therapien (BCRT) Berlin, Deutschland; ¹³Charité - Universitätsmedizin Berlin CC11: Med. Klinik m.S. Kardiologie Berlin, Deutschland; ¹⁴Abteilung für Zelluläre und Translationale Physiologie, Molekulare und Experimentelle Kardiologie,, Institut für Physiologie, Institut für Forschung und Lehre (IFL), Ruhr-Universität Bochum Bochum, Deutschland; ¹⁵University of Antwerp Department of Pharmaceutical Sciences Antwerp, Belgien; ¹⁶Universitätsklinikum Münster Institut für Physiologie II Münster, Deutschland; ¹⁷Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland

Aims: This study aimed to evaluate the effects of stimulating the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathway using the sGC stimulator BAY 41-8543 on left ventricular (LV) diastolic function and oxidative stress in rodent models and myocardial biopsies from patients with heart failure with preserved ejection fraction (HFpEF).

Methods and Results: Chronic (4-week) pharmacological activation of sGC was assessed in 15-week-old male Dahl salt-sensitive rats with diastolic dysfunction (DD) and in control rats (n = 8–12 per group). Acute, ex vivo sGC stimulation was also performed in myocardial biopsies from HFpEF patients. Parameters of endothelial function, inflammatory activation, oxidative stress, NO bioavailability, and sGC–cGMP–PKG signaling were analyzed alongside cardiomyocyte mechanical properties. Chronic sGC stimulation significantly improved elevated LV end-diastolic pressure, ventricular stiffness, arterial elastance, and endothelial dysfunction in DD rats. Immunohistochemistry revealed a shift of sGC localization from a diffuse cytoplasmic pattern to sarcomeric association following stimulation. BAY 41-8543 treatment also reduced myocardial fibrosis, collagen gene expression, oxidative stress, and inflammation, while restoring NO bioavailability, cGMP levels, and PKG activity. Enhanced PKG-mediated phosphorylation of titin accounted for decreased cardiomyocyte stiffness in DD. Similarly, acute sGC stimulation in human HFpEF biopsies improved cardiomyocyte compliance via increased titin phosphorylation and reduced oxidative stress.

Conclusion: Chronic pharmacological stimulation of sGC ameliorates diastolic dysfunction by restoring NO–sGC–cGMP–PKG signaling and reducing oxidative stress, suggesting sGC activation as a potential therapeutic strategy for patients with HFpEF.