The Regulatory Effects of SIRT1 Agonists on Myocardial Cell Ferroptosis via Modulation of Mitophagy in Rats with Chronic Heart Failure
LIU Zhanhao
ZHONG Hao
YUAN Xue
ZHANG Fangfang
HOU Xiaohua
Abstract：Objective:To investigate that silent information regulator 1(SIRT1)agonists inhibit cardiomyocyte ferroptosis in rats with chronic heart failure(CHF)by modulating mitophagy levels.Methods:A total of sixty rats were randomly divided into the control group,the model group,the SIRT1 agonist SRT 1460(50 mg/kg)group,the mitochondrial autophagy inducer Olaparib(10 mg/kg)group,and the SRT 1460/Olaparib combination group,with 12 rats in each group.During a four-week period,rats in the model group received intraperitoneal injections of Adriamycin hydrochloride(ADMH,1.5 mg/kg)twice a week.During the modeling period,relative doses of drugs were intraperitoneally injected in the SRT 1460 group,the Olaparib group,and the SRT 1460+Olaparib group,while the control group was injected with normal saline once a day.Hematoxylin-eosin(HE)staining was used to evaluate the morphology of cardiomyocytes.Enzyme-linked immunosorbent assay(ELISA)was used to detect serum troponin I(cTnI),creatine kinase isoenzyme(CK-MB)and N-terminal pro-brain natriuretic peptide(NT-proBNP)levels.The mitochondrial membrane potential(MMP)of rat cardiomyocytes was detected using JC-1 staining.Immunofluorescence double staining for Tom20 and Drp1 was used to observe mitochondrial fission in cardiomyocytes.Western Blot was used to detect the mitochondrial fission markers[dynamin-related protein 1(Drp1)and Fission 1 protein(Fis1)],fusion markers[mitochondrial fusion protein 1(Mfn1),optic atrophy protein 1(OPA1)],and ferroptosis markers[solute carrier family 7 member 11(SLC7A11),glutathione peroxidase 4(GPX4)]in rat myocardial tissue.The mitochondrial structure of rat cardiomyocytes was observed by transmission electron microscope.Results:Compared with the control group,more extensive myocardial fiber necrosis was observed in the myocardial cells of CHF rats.In addition,the serum levels of cTnI and NT-proBNP,as well as the fluorescence intensities of Drp1 and Tom20 in myocardial tissue,significantly elevated.Moreover,the expression levels of Drp1 and Fis1 proteins also increased(P＜0.01).Whereas in myocardial tissue,expression of Mfn1,OPA1,SLC7A11,GPX4,and MMP significantly decreased(P＜0.01).Additionally,some mitochondria in the model group showed mild swelling and signs of autophagy.SRT 1460 treatment reduced the expression trend observed in the above results in the model group(P＜0.01).Olaparib negated the improvement effect of SRT 1460 on the above results in the model group rats.Conclusion:SIRT1 agonists inhibit ferroptosis of cardiomyocytes in CHF rats by regulating mitochondrial fission and fusion through the mitochondrial autophagy pathway in cardiomyocytes.
Keywords：chronic heart failuresilent information regulator related enzyme 1mitophagycardiomyocytesferroptosisexperimental study
Publication Date：2025-08-25
Online Publishing Date：2025-09-10(First online date of this platform, not the publication date of the document)
Pages：7( 2474-2480 )