Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity maintaining AMPK/UCP2 pathway.
10.1016/j.apsb.2019.03.003
- Author:
Can HU
1
;
Xin ZHANG
1
;
Wenying WEI
1
;
Ning ZHANG
1
;
Haiming WU
1
;
Zhenguo MA
1
;
Lingli LI
1
;
Wei DENG
1
;
Qizhu TANG
1
Author Information
1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
- Publication Type:Journal Article
- Keywords:
4-HNE, 4-hydroxynonenal;
ACC, acetyl-CoA carboxylase;
AMPKα;
AMPKα, 5′-AMP-activated protein kinase α;
ANOVA, analysis of variance;
Apoptosis;
BAX, BCL-2-associated X protein;
BCA, bicinchoninic acid;
BCL-2, B-cell lymphoma 2;
C-caspase 3, cleaved-caspase3;
CCK-8, cell counting kit 8;
CK-MB, creatine kinase isoenzymes;
DCFH-DA, 2′,7′-dichlorodihydrofluorescein diacetate;
DHE, dihydroethidium;
DMEM, Dulbecco׳s modified Eagle׳s medium;
DOX, doxorubicin;
FBS, fetal bovine serum;
FS, fractional shortening;
GAPDH, glyceraldehyde 3-phosphate dehydrogenase;
HW, heart weight;
LDH, lactate dehydrogenase;
MDA, malondialdehyde;
Matrine;
Oxidative stress;
PPARs, peroxisomal proliferators-activated receptors;
ROS, reactive oxygen species;
SOD2, superoxide dismutase 2;
T-caspase3, total-caspase3;
TL, tibia length;
TUNEL, TdT-mediated dUTP nick end-labelling;
Top2, topoisomerase-II;
UCP2;
UCP2, uncoupling protein 2;
cTnT, cardiac isoform of Tropnin T
- From:
Acta Pharmaceutica Sinica B
2019;9(4):690-701
- CountryChina
- Language:English
-
Abstract:
Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9C2 cells were used to verify the effect of matrine . DOX injection triggered increased generation of reactive oxygen species (ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2 (UCP2) downregulation, and UCP2 inhibition by genipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 5'-AMP-activated protein kinase 2 () deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9C2 cells apoptosis and oxidative stress level activating AMPK/UCP2, which were blunted by either AMPK or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity maintaining AMPK/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.
