Soluble guanylate cyclase stimulation improves cardiac function and mitochondrial activity in a rat model of early-stage heart failure with preserved ejection fraction

Targeting cardiac mitochondrial dysfunction and cardiac metabolic reprogramming is critical for improving chronic heart failure (HF) treatment. While the soluble guanylate cyclase stimulator vericiguat has shown promise in treating HF with reduced ejection fraction (HFrEF), its effects on HF with preserved ejection fraction (HFpEF), particularly on myocardial bioenergetics, remain undefined. This study aimed to clarify the effects of vericiguat on cardiac function and metabolism in a preclinical model of early-stage HF. Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to receive standard care (n = 10) or vericiguat (3 mg/kg/d p.o.) (n = 10) treatment for 4 weeks. ZSF1 lean rats (n = 10) served as controls. Vericiguat improved diastolic function, reduced cardiac hypertrophy and fibrosis and enhanced cardiac mitochondrial basal respiration, upregulating the levels of several mitochondrial electron transport chain proteins from complexes I, II, III and V, along with the ADP/ATP translocase 1 mRNA levels, and partially reversing mitochondrial cristae diffuse dissolution observed in obese control rat hearts. Vericiguat treatment increased cardiac levels of phosphoproteins involved in the pentose phosphate pathway (PPP) (6-phosphogluconolactonase and 6-phosphogluconate dehydrogenase) and in the Krebs cycle (malate dehydrogenase and aspartate aminotransferase), while normalizing the mRNA levels of the master regulator of calcium uptake by the mitochondria (MICU1). Furthermore, vericiguat restored the cardiac levels of key metabolites of the PPP such as 6-phosphogluconate, D-ribose 5-phosphate, and arginine, that were diminished in the obese control group. In conclusion, vericiguat elicits beneficial functional and metabolic responses at cardiac level in an animal model of early-stage HFpEF.

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Journal
Biomedicine & Pharmacotherapy
Published
2025-08-12
DOI
https://doi.org/10.1016/j.biopha.2025.118439
Citations
1
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.81

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article

Soluble guanylate cyclase stimulation improves cardiac function and mitochondrial activity in a rat model of early-stage heart failure with preserved ejection fraction

Inês N. Alves, Cláudia Sousa-Mendes, Manuel Otero-Santiago, Francisca Lago et al.
1 citations
Biomedicine & Pharmacotherapy
Mitochondrial Function and Pathology
0.81
article

Soluble guanylate cyclase stimulation improves cardiac function and mitochondrial activity in a rat model of early-stage heart failure with preserved ejection fraction

Inês N. Alves, Cláudia Sousa-Mendes, Manuel Otero-Santiago, Francisca Lago, Alana Aragón‐Herrera, Manuel Portolés, Esther Roselló‐Lletí, Oreste Gualillo, Alexandre Gonçalves, José Ramón González‐Juanatey, Susana B. Bravo, Sandra Feijóo‐Bandín, Estefanía Tarazón, Sandra Moraña‐Fernández, Inês Falcão‐Pires, Juliana Morais, Karen Thomitzek, Peter Sandner, Xocas Vázquez‐Abuín, Alexandre Rodrigues, Carlos Tilves-Bellas, Javier García-Seara, Pablo de la Fuente-López
article en
1 citations

Abstract

Targeting cardiac mitochondrial dysfunction and cardiac metabolic reprogramming is critical for improving chronic heart failure (HF) treatment. While the soluble guanylate cyclase stimulator vericiguat has shown promise in treating HF with reduced ejection fraction (HFrEF), its effects on HF with preserved ejection fraction (HFpEF), particularly on myocardial bioenergetics, remain undefined. This study aimed to clarify the effects of vericiguat on cardiac function and metabolism in a preclinical model of early-stage HF. Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to receive standard care (n = 10) or vericiguat (3 mg/kg/d p.o.) (n = 10) treatment for 4 weeks. ZSF1 lean rats (n = 10) served as controls. Vericiguat improved diastolic function, reduced cardiac hypertrophy and fibrosis and enhanced cardiac mitochondrial basal respiration, upregulating the levels of several mitochondrial electron transport chain proteins from complexes I, II, III and V, along with the ADP/ATP translocase 1 mRNA levels, and partially reversing mitochondrial cristae diffuse dissolution observed in obese control rat hearts. Vericiguat treatment increased cardiac levels of phosphoproteins involved in the pentose phosphate pathway (PPP) (6-phosphogluconolactonase and 6-phosphogluconate dehydrogenase) and in the Krebs cycle (malate dehydrogenase and aspartate aminotransferase), while normalizing the mRNA levels of the master regulator of calcium uptake by the mitochondria (MICU1). Furthermore, vericiguat restored the cardiac levels of key metabolites of the PPP such as 6-phosphogluconate, D-ribose 5-phosphate, and arginine, that were diminished in the obese control group. In conclusion, vericiguat elicits beneficial functional and metabolic responses at cardiac level in an animal model of early-stage HFpEF.

Biomedicine & PharmacotherapyVol. 191
Universidade do Porto (PT), Instituto de Salud Carlos III (ES), Complejo Hospitalario Universitario de Santiago (ES), Centro de Investigación Biomédica en Red (ES), Complexo Hospitalario Universitario A Coruña (ES), Instituto de Investigación Sanitaria de Santiago (ES), Bayer (Germany) (DE), Universidade Nova de Lisboa (PT)
Bayer, Sociedad Española de Cardiología, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela, Università degli Studi di Firenze, Axencia Galega de Innovación, Xunta de Galicia, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 25%
Mitochondrial Function and Pathology
0.81
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