Entresto protected the cardiomyocytes and preserved heart function in cardiorenal syndrome rat fed with high-protein diet through regulating the oxidative stress and Mfn2-mediated mitochondrial functional integrity
This study tested the hypothesis that Entresto (En) therapy protected the cardiomyocytes and heart function in cardiorenal syndrome (CRS) rats fed with high-protein diet (HPD) through regulating the oxidative-stress and Mfn2-mediated mitochondrial functional integrity. En (12.5 μM for the in-vitro s...
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| Autores principales: | , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Elsevier
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/36b31e3bfbd24590aa7e28d37939ce6e |
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| Sumario: | This study tested the hypothesis that Entresto (En) therapy protected the cardiomyocytes and heart function in cardiorenal syndrome (CRS) rats fed with high-protein diet (HPD) through regulating the oxidative-stress and Mfn2-mediated mitochondrial functional integrity. En (12.5 μM for the in-vitro study) protected the H9C2-cells against H2O2-induced cell apoptosis, whereas stepwise-increased H2O2 concentrations induced a significant increase in protein expressions of Mfn2/phosphorylated (p)-DRP1/mitochondrial-Bax in H9C2-cells. En downregulated H2O2-induced mitochondrial fission/upregulated mitochondrial fusion and deletion of Mfn2 gene (i.e., shMfn2) to significantly reduce H2O2-induced ROS production. En significantly suppressed and shMfn2 further significantly suppressed both H2O2-reduced mitochondrial-membrane potential and H2O2-induced ROS production/cell apoptosis/mitochondrial damage/mitochondrial-Bax released from mitochondria in H9C2 cells. En significantly reduced protein expressions of Mfn2 and p-DRP1. Additionally, En significantly suppressed and shMfn2 further significantly suppressed the protein expressions of mitochondrial-damaged (DRP1)/oxidative-stress (NOX-1/NOX-2)/apoptosis (mitochondrial-Bax/caspase-3/PARP)/autophagic (LC3B-II/LC3B-I) biomarkers (all p < 0.01). Rats were categorized into group 1 [sham-control + high-protein-diet (HPD)], group 2 (CRS + HPD) and group 3 (CRS+ HPD + En/100 mg/kg/day). By day 63 after CRS induction, the LVEF was significantly lower in group 3 and more significantly lower in group 2 than in group 1, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2/p22phox/oxidized protein)/apoptotic (mitochondrial-Bax/caspase-3/PARP), fibrotic (Smad-3/TGF-ß), autophagic (Beclin-1/Atg5/ratio of LC3B-II/LC3B-I) and mitochondrial-damaged (DRP1/cyclophilin-D/cytosolic-cytochrome-C) biomarkers exhibited an opposite pattern of LVEF among the groups. Downregulation of Mfn2 by En or shMfn2 in cardiomyocytes avoided H2O2 damage and En improved the cardiac function in HPD-feeding CRS rat via adjusting Mfn2-mediated mitochondrial functional integrity. |
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