Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation.
Acta Pharm Sin B
; 9(4): 782-793, 2019 Jul.
Article
en En
| MEDLINE
| ID: mdl-31384538
The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague-Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.
3AB, 3-aminobenzamide; ADR, adriamycin; ANOVA, one-way analysis of variance; Apoptosis; CHR, chrysophanol; CMC-Na, sodium carboxymethyl; CO, cardiac output; Cardiotoxicity; Chrysophanol; Cyt c, Cytochrome c; DOX, doxorubicin; Doxorubicin; EF, ejection fraction; FBS, fetal bovine serum; FS, fractional shortening; HE, hematoxylin-eosin; HR, heart rate; IVSd, end-diastolic interventricular septum; IVSs, end-systolic interventricular septum; LV, end-systolic volume; LVEDV, LV end-diastolic volume; LVIDd, LV end-diastolic internal diameter; LVIDs, LV end-systolic internal diameter; LVPWd, LV end-diastolic posterior wall thickness; LVPWs, LV end-systolic posterior wall thickness; Mitochondria; NS, normal saline; PAR, polymers of ADP-ribose; PARP1, poly(ADP-ribose) polymerase 1; PARylated, poly(ADP-ribosyl)ated; PARylation; PARylation, poly(ADP-ribosyl)ation; PBS, phosphate-buffered saline; RCR, respiratory control ratio; ROS, reactive oxygen species; Rh123, rhodamine 123; SD, SpragueDawley; TUNEL, TdT-mediated dUTP nick end labeling; VDAC1, voltage dependent anion channel 1
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Acta Pharm Sin B
Año:
2019
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos