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 - 13/11/21
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Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
The proposed underlying mechanism of entresto therapy in protecting the heart and kidney against cardiorenal syndrome (CRS). The in vitro results demonstrated that downregulation of Mfn2 by entresto or shMfn2 ameliorated H2O2-caused mitochondrial and cardiomyocyte damage. Additionally, entresto preserved the heart function in high-protein diet-feeding CRS rat via adjusting Mfn2-mediated mitochondrial functional integrity, downregulating oxidative stress, cell-stress signaling and mitophagy.
Highlights |
• | Entresto (En) regulated mitochondrial fusion via downregulating Mfn2. |
• | Entresto suppressed oxidative-stress & cell-stress signaling via regulating Mfn2. |
• | Downregulated Mfn2 was more effective than En on ROS suppression. |
• | En-mediated Mfn2 preserved mitochondrial and heart functions. |
Keywords : Entresto, Mitofusin 2, Oxidative stress, Mitochondrial damage, Left ventricular ejection fraction (LVEF), Cardiorenal syndrome
Plan
Vol 144
Article 112244- décembre 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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