Publicação

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

Detalhes bibliográficos
Resumo:	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.
Autores principais:	Vázquez-Abuín, Xocas
Outros Autores:	Moraña-Fernández, Sandra; Aragón-Herrera, Alana; Sandner, Peter; Thomitzek, Karen; García-Seara, Javier; Bravo, Susana B.; Otero-Santiago, Manuel; de la Fuente-López, Pablo; Tilves-Bellas, Carlos; Rodrigues, Alexandre; Gonçalves, Alexandre; Pereira Morais, Juliana; Morais, Juliana; Alves, Inês N.; Sousa-Mendes, Cláudia; Falcão-Pires, Inês; Tarazón, Estefanía; Roselló-Lletí, Esther; Portolés, Manuel; Gualillo, Oreste; González-Juanatey, José Ramón; Feijóo-Bandín, Sandra; Lago, Francisca
Assunto:	Diastolic dysfunction Heart failure with preserved ejection fraction Mitochondria Proteome Soluble guanylate cyclase stimulator ZSF1 Pharmacology
Ano:	2025
País:	Portugal
Tipo de documento:	artigo
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade Nova de Lisboa
Idioma:	inglês
Origem:	Repositório Institucional da UNL

Descrição
Resumo:	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.