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

Clin Res Cardiol (2026). DOI 10.1007/s00392-026-02870-1
M. Herwig (Bochum)¹, Á. Kovács (Debrecen)², A. B. Gevaert (Antwerp)³, M. Sieme (Bochum)¹, S. Delalat (Bochum)¹, S. Zhazykbayeva (Bochum)¹, D. Kolijn (Bochum)¹, A. J. Leloup (Antwerp)⁴, P. Fransen (Antwerp)⁵, G. Á. Fülöp (Debrecen)⁶, M. Lodí (Bochum)¹, D. Czuriga (Debrecen)⁷, Z. F. Kisvárday (Debrecen)⁸, L. van Heerebeek (Amsterdam)⁹, P. Sandner (Wuppertal)¹⁰, Z. Papp (Debrecen)⁶, S. Van Linthout (Berlin)¹¹, C. Tschöpe (Berlin)¹², A. Mügge (Bochum)¹, G. W. De Keulenaer (Antwerp)¹³, W. A. Linke (Münster)¹⁴, N. Hamdani (Bochum)^1
1Medical 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; ²Division of Clinical Physiology Department of Cardiology, Faculty of Medicine Debrecen, Deutschland; ³Department of Pharmaceutical Sciences, Laboratory of Physiopharmacology, University of Antwerp Antwerp, Belgien; ⁴University of Antwerp Laboratory of Physiopharmacology Antwerp, Belgien; ⁵University of Antwerp Department of Pharmaceutical Science Antwerp, Ungarn; ⁶Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen Debrecen, Ungarn; ⁷The Royal Brompton and Harefield NHS Trust Division of Cardiology Debrecen, Ungarn; ⁸University of Debrecen Department of Anatomy Debrecen, Deutschland; ⁹From the Heart Center, Division Cardiology of the OLVG Hospital Department of Cardiology Amsterdam, Niederlande; ¹⁰Bayer AG Drug Discovery Cardiology Wuppertal, Deutschland; ¹¹Charité - Universitätsmedizin Berlin BIH Center für regenerative Therapien (BCRT) Berlin, Deutschland; ¹²Charité - Universitätsmedizin Berlin CC11: Med. Klinik m.S. Kardiologie Berlin, Deutschland; ¹³University of Antwerp Department of Pharmaceutical Sciences Antwerp, Belgien; ¹⁴Universitätsklinikum Münster Institut für Physiologie II Münster, 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.