PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades

Abstract

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.

Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats

“…Presently, we observed that exogenous hsp22 obviously augmented the AMPK phosphorylation at Thr172, whereas dorsomorphin evidently counteracted hsp22-mediated protection against EBI after SAH by worsening neurological impairment and brain edema, aggravating mitochondrial fission and the outbreak of oxidative stress, and suppressing mitochondrial biogenesis and apoptotic cascades. More fundamentally, it is well established that activating AMPK by phosphorylation at Thr172 site upregulates PGC1α in skeletal muscle [ 55 ] and cardiovascular system [ 56 ], as well as brain [ 57 ]. Accordingly, it's logical to conjecture that hsp22 may alter PGC1α activity by enhancing AMPK phosphorylation at the same site.…”

Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction

“…At the molecular level, two mechanisms involved in how resveratrol attenuates hyperlipemia-related cardiomyocyte injury have been reported: one is driven by upregulation of antioxidative factors and the other involves downregulation of pro-inflammation cytokines. For example, resveratrol attenuates lipid peroxidation (Jalili et al, 2019) through modulation of several antioxidative signaling pathways such as Nrf2 (Zhuang et al, 2019), Sirt1 (Liu et al, 2019a), Akt/mTOR (Radwan and Karam, 2020), and ERK1/2 (Fathalipour et al, 2019). In addition, the mRNA expression of inflammatory cytokines in diabetic mice are largely inhibited by resveratrol (Xing et al, 2020).…”

Pterostilbene Attenuates Cocultured BV-2 Microglial Inflammation-Mediated SH-SY5Y Neuronal Oxidative Injury via SIRT-1 Signalling

“…Previously, we have also found that SIRT-1/NF- κ B signalling could attenuate inflammatory injury in experimental SAH models [ 36 ]. Interestingly, PTE has been proved as a potent SIRT-1 activator in different cells, including hepatic cells [ 37 ], cardiomyocytes [ 38 ], and skeletal muscle cells [ 39 ]. However, the role of SIRT-1 signalling in microglia after PTE treatment and the relationship between microglial inflammation and neuronal oxidative injury in the PTE mediated neuroprotection have not been well investigated.…”

“…Therefore, it could be speculated that SIRT-1 is an intracellular modulator of microglia-mediated inflammation. Multiple studies have revealed that PTE could activate SIRT-1 signalling in hepatic [37], myocardial [38], and skeletal muscle cells [39]. Interestingly, a study reported that a two-month diet of PTE or its analogue resveratrol did not increase SIRT-1 expression or the downstream signalling activation, whereas it increased peroxisome proliferator-activated receptor (PPAR) α expression, and thus modulated cellular stress, inflammation, and AD pathology [44].…”