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Soluble Guanylate Cyclase Stimulator, BAY41-8543: A Promising Approach for the Treatment of Chronic Heart Failure Caused by Pressure and Volume Overload

A. Martišková, M. Sýkora, N. Andelová, M. Ferko, O. Gawrys, K. Andelová, P. Kala, L. Červenka, B. Szeiffová Bačová

. 2025 ; 13 (2) : e70087. [pub] -

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25009310

Grant support
NU23J-02-00015 Ministry of the Czech Republic
22-0264 Slovak Research and Development Agency
21-0410 Slovak Research and Development Agency
VV-MVP-24-0278 Slovak Research and Development Agency
09I03-03 V04-00437 Scholarships for Excellent R2-R4 Researchers
LX22NPO5104 National Institute for Research of Metabolic and Cardiovascular Diseases
2/0016/23 Scientific Grant Agency of the Ministry of Education, Research, Development and Youth of the Slovak Republic and Slovak Academy of Sciences
2/0006/23 Scientific Grant Agency of the Ministry of Education, Research, Development and Youth of the Slovak Republic and Slovak Academy of Sciences
2/0133/24 Scientific Grant Agency of the Ministry of Education, Research, Development and Youth of the Slovak Republic and Slovak Academy of Sciences

Heart failure (HF) is a leading cause of morbidity and mortality, often driven by prolonged exposure to pathological stimuli such as pressure and volume overload. These factors contribute to excessive oxidative stress, adverse cardiac remodeling, and dysregulation of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway. Given the urgent need for effective treatments, this study investigated the potential of sGC stimulators to mitigate HF progression. We utilized male hypertensive Ren-2 transgenic (TGR) rats and a volume-overload HF model induced by an aortocaval fistula (ACF). Rats received the sGC stimulator BAY 41-8543 (3 mg/kg/day) for 30 weeks, while normotensive Hannover Sprague-Dawley rats served as controls. At the study endpoint (40 weeks of age), left ventricular tissue was analyzed using mass spectrometry, Western blotting, and histological assessment. TGR rats treated with sGC stimulators exhibited a significant increase in key antioxidant proteins (SOD1, CH10, ACSF2, NDUS1, DHE3, GSTM2, and PCCA), suggesting enhanced resistance to oxidative stress. However, sGC stimulator treatment also upregulated extracellular matrix remodeling markers (MMP-2, TGF-β, and SMAD2/3), which are typically associated with fibrosis. Despite this, Masson's trichrome staining revealed reduced collagen deposition in both TGR and TGR-ACF rats receiving sGC stimulators. Notably, all untreated TGR-ACF rats succumbed before the study endpoint, preventing direct assessment of sGC stimulator effects in advanced HF. These findings highlight the therapeutic potential of sGC stimulators in HF, particularly through their antioxidant effects. However, their concurrent influence on fibrosis warrants further investigation to optimize treatment strategies.

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