Abstract
Mitochondrial reactive oxygen species (mtROS) homeostasis plays an essential role in preventing oxidative injury in endothelial cells, an initial step in atherogenesis. Resveratrol (RSV) possesses a variety of cardioprotective activities, however, little is known regarding the effects of RSV on mtROS homeostasis in endothelial cells. Sirt3 is a mitochondrial deacetylase, which plays a key role in mitochondrial bioenergetics and is closely associated with oxidative stress. The goal of the study is to investigate whether RSV could attenuate oxidative injury in endothelial cells via mtROS homeostasis regulation through Sirt3 signaling pathway. We found that pretreatment with RSV suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, inhibiting cell apoptosis, repressing collapse of mitochondrial membrane potential and decreasing mtROS generation. Moreover, the enzymatic activities of isocitrate dehydrogenase 2 (IDH2), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (SOD2) as well as deacetylation of SOD2 were increased by RSV pretreatment, suggesting RSV notably enhanced mtROS scavenging in t-BHP-induced endothelial cells. Meanwhile, RSV remarkably reduced mtROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of forkhead box O3A (FoxO3A)-mediated mitochondria-encoded gene expression of ATP6, CO1, Cytb, ND2 and ND5, thereby leading to increased complex I activity and ATP synthesis. Furthermore, RSV activated the expressions of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and Sirt3, as well as estrogen-related receptor-α (ERRα)-dependent Sirt3 mRNA transcription, which were abolished in the presence of AMPK inhibitor and AMPK, PGC-1α or Sirt3 siRNA transfection, indicating the effects of RSV on mtROS homeostasis regulation were dependent on AMPK-PGC-1α-ERRα-Sirt3 signaling pathway. Our findings indicated a novel mechanism that RSV-attenuated oxidative injury in endothelial cells through the regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt3 signaling pathway.
Highlights
Resveratrol (3, 4′, 5-trihydroxystilbene, RSV) is a polyphenolic compound found mainly in the skins of grapes, and berry fruits, and in peanuts and red wine
It has been reported that Sirt[3] functions as a downstream target of peroxisome proliferator-activated receptor (PPARγ) coactivator-1α (PGC-1α), which is directly regulated by adenosine monophosphate-activated protein kinase (AMPK), thereby stimulating deacetylation of mitochondrial enzymes involved in mtROS homeostasis and activation of forkhead box O3A (FoxO3A)-mediated mitochondrial DNA transcription to attenuate oxidative damage.[12,15,16]
Sirt[3] siRNA transfection decreased the stimulatory effects of RSV on the mitochondrial DNA (mtDNA) transcription and the coded gene expressions, along with the complex I activity and ATP content, which are possibly attributable to decreased deacetylation of FoxO3A mediated by silent mating-type information regulation homolog 3 (Sirt3).21 These results clearly indicated that RSV pretreatment caused Sirt[3] enrichment in mitochondria, which was required for the activation of mtDNA transcription and ATP synthesis, leading to a reduction of mtROS as the byproduct of oxidative phosphorylation (OXPHOS) in endothelial cells
Summary
Resveratrol (3, 4′, 5-trihydroxystilbene, RSV) is a polyphenolic compound found mainly in the skins of grapes, and berry fruits (cranberry, strawberry, mulberry, etc.), and in peanuts and red wine. Cell Death and Disease oxidative damage through regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt[3] signaling pathway. These results provide new evidence regarding the vascular protective effects of RSV and may open new avenues for finding new drugs that can be applied to endothelial protection and AS prevention
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