Early treatment with combination of SS31 and entresto effectively preserved the heart function in doxorubicin-induced dilated cardiomyopathic rat - 03/09/21
, Hon-Kan Yip b, c, g, h, i, j, ⁎ Bienvenue sur EM-consulte, la référence des professionnels de santé.
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Abstract |
Background |
This study tested the hypothesis that early administration of SS31 and entresto (En) was superior to either one alone on preserving the heart function in setting of dilated cardiomyopathy (DCM) induced by doxorubicin (Dox) [accumulated dosage of 12.5 mg/kg/administered by intraperitoneal (IP) at 4 separated time points within 20 days] in rat.
Methods and results |
Adult-male SD rats (n = 40) were equally categorized into groups 1 (sham-control), 2 (DCM), 3 (DCM + SS31/0.7 mg/kg/day/IP, since day-14 after DCM induction to day-60), 4 [DCM + En (30 mg/kg/day/orally since day-14 after DCM induction to day-60)] and 5 (DCM + combined SS31-En), and animals were euthanized by day 60. By day 60, left-ventricular ejection-fraction (LVEF) was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3 and 4 (all p < 0.0001), but it showed no difference between groups 3/4. The microscopic study showed that the fibrosis area/cardiomyocyte size and DNA-damaged (γ-H2AX+)/inflammatory (CD14+//CD68+) markers, and flow analysis of inflammatory (Ly6G+/MPO+/CD11b/c+) and early/late apoptosis (AN-V+/PI-//AN-V+/PI+) cells exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). The protein expressions of inflammatory upstream (TLR2/TLR4/MyD88/Mal/ TRAF6/IKK-α/IKK-ß) and downstream (p-NF-κb/TNF-α/IL-1ß/MMP-9), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/cytosolic cytochrome-C/cyclophilin-D/DRP1) and autophagic/apoptotic (ratio of LC3B-II/LC3B-I and mitochondrial-Bax/caspase3/9) signaling pathways also exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001).
Conclusion |
Combined SS31-En therapy was superior to either one alone on protecting the heart structural and functional integrities against Dox-induced DCM damage.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
The proposed underlying mechanism of SS31-En treatment on preserving the LVEF in setting of Dox-induced DCM. The therapeutic potentials of SS31-En on protecting the functional and structural integrities of rodent heart are mainly through suppressing upstream and downstream inflammatory, oxidative stress and mitochondrial-damaged signaling pathways.
Dox= doxorubicin; En= entresto; DCM= dilated cardiomyopathy; ROS= reactive oxygen species.
Highlights |
● | Doxorubicin (Dox) commonly induced dilated cardiomyopathy (DCM). |
● | Currently, treatment for Dox-induced DCM and HF remains regrettably lacking. |
● | Dox-induced DCM via upregulating oxidative stress, DNA and mitochondrial damage. |
● | SS31-Entresto preserved cardiac function in setting of Dox-induced DCM. |
Keywords : Dilated cardiomyopathy, SS31, Doxorubicin, Entresto, Inflammation, Oxidative stress, Cell death
Plan
Vol 141
Article 111886- septembre 2021 Retour au numéro
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