Resveratrol Attenuate Myocardial Injury by Inhibiting Ferroptosis Via Inducing KAT5/GPX4 in Myocardial Infarction

Abstract

Myocardial infarction (MI) is a coronary artery-related disease and ranks as the leading cause of sudden death globally. Resveratrol (Res) is a bioactive component and has presented antioxidant, anti-inflammatory and anti-microbial properties. However, the effect of Res on ferroptosis during MI progression remains elusive. Here, we aimed to explore the function of Res in the regulation of ferroptosis and myocardial injury in MI. We observed that the treatment of Res attenuated the MI-related myocardium injury and fibrosis in the rats. The expression of collagen 1 and α-SMA was induced in MI rats, in which the treatment of Res could decrease the expression. Treatment of Res suppressed the levels of IL-6 and IL-1β in MI rats. The GSH levels were inhibited and MDA, lipid ROS, and Fe2+ levels were induced in MI rats, in which the treatment of Res could reverse the phenotypes. Meanwhile, the expression of GPX4 and SLC7A11 was reduced in MI rats, while the treatment of Res could rescue the expression in the model. Meanwhile, Res relieved oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury. Importantly, Res repressed OGD-induced cardiomyocyte ferroptosis in vitro. Mechanically, we identified that Res was able to enhance GPX4 expression by inducing KAT5 expression. We confirmed that KAT5 alleviated OGD-induced cardiomyocyte injury and ferroptosis. The depletion of KAT5 or GPX4 could reverse the effect of Res on OGD-induced cardiomyocyte injury. Thus, we concluded that Res attenuated myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Our finding provides new evidence of the potential therapeutic effect of Res on MI by targeting ferroptosis.

Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis

“…In 2009, Elif Tatlidede et al demonstrated that RSV treatment notably raised cardiac GSH contents and suppressed oxidant responses in DOX-processed rats; Simultaneously, it ameliorated DOX-induced deterioration of cardiac function and myocardial injury [192]. In the following decade, many researchers verified in various models of myocardial injury that RSV can exert an antioxidant effect and protect the myocardium by increasing the level of GSH and upregulating the activity of GSH-dependent antioxidant enzymes [193][194][195][196][197]. Moreover, they revealed that the mechanism by which RSV enhances the GSH system involves the AMPK signaling pathway, the Nrf2 signaling pathway, the Sirt1 pathway, noncoding RNA (miR-149) and the KAT5 gene [193][194][195][196][197].…”

“…In the following decade, many researchers verified in various models of myocardial injury that RSV can exert an antioxidant effect and protect the myocardium by increasing the level of GSH and upregulating the activity of GSH-dependent antioxidant enzymes [193][194][195][196][197]. Moreover, they revealed that the mechanism by which RSV enhances the GSH system involves the AMPK signaling pathway, the Nrf2 signaling pathway, the Sirt1 pathway, noncoding RNA (miR-149) and the KAT5 gene [193][194][195][196][197]. In addition, RSV can suppress the occurrence of ferroptosis in the myocardium by increasing SLC7A11/GSH and GPX4 [193,195].…”

“…Moreover, they revealed that the mechanism by which RSV enhances the GSH system involves the AMPK signaling pathway, the Nrf2 signaling pathway, the Sirt1 pathway, noncoding RNA (miR-149) and the KAT5 gene [193][194][195][196][197]. In addition, RSV can suppress the occurrence of ferroptosis in the myocardium by increasing SLC7A11/GSH and GPX4 [193,195]. In general, consistent with preclinical studies, RSV supplementation (500 mg/day, P.O for 4 weeks) raised erythrocyte PPAR-γ and Sirt1 expression and serum TAC and attenuated the total/HDL cholesterol ratio in CHD patients with type 2 diabetes [198].…”

miR-16-5p Regulates Ferroptosis by Targeting SLC7A11 in Adriamycin-Induced Ferroptosis in Cardiomyocytes

“…However, under certain pathological conditions, the transport capacity of SLC7A11 and the activity of GPX4 decreased, finally inducing ferroptosis. 27 SLC7A11 is expressed in various tissues and downregulated in pathological conditions. Similarly to our results, Li et al 28 recently reported that GPX4 expression decreased in ADR-induced myocardial injury in mice, suggesting that upstream SLC7A11 may participate in the ferroptosis of ADR-induced myocardial injury in mice.…”

Suffruticosol C-Mediated Autophagy and Cell Cycle Arrest via Inhibition of mTORC1 Signaling

“…According to our results, we found that suffruticosol C has a better inhibitory effect on cell viability than resveratrol at the same concentration. A large number of studies suggested that resveratrol plays a crucial role in autophagy, cell cycle, ferroptosis, and apoptosis [ 24 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. However, in our study, we found that suffruticosol C, unlike resveratrol, only has a specific regulatory effect on autophagy and the cell cycle, but it has no effect on apoptosis and ferroptosis.…”