Research Paper Volume 11, Issue 22 pp 10061—10073
PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades
- 1 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
- 2 Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710038, China
received: July 23, 2019 ; accepted: October 28, 2019 ; published: November 16, 2019 ;https://doi.org/10.18632/aging.102418
How to Cite
Copyright © 2019 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the action and detailed mechanism of pterostilbene on DOX-treated cardiomyocytes. We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Pterostilbene markedly alleviated the DOX exposure-induced acute myocardial injury. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) in vivo. Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.
AMPK: adenosine monophosphate activated protein kinase; DOX: doxorubicin; NRF1: nuclear respiratory factor 1; PGC1α: peroxisome proliferator-activated receptor coactivator 1α; UCP2: uncoupling protein 2.