Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury.
Methods:
Eight-week high-fat diet (HFD) Sprague-Dawley rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for an in vivo and in vitro lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific stimulator of interferon genes (STING) knockdown rat (Stingmyo-KD) with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis-related proteins, and STING pathway-related proteins in H9c2 cells/myocardium were detected.
Results:
HFD rats with a ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation, and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown of the expression of STING could reduce PA-induced cell death, lipid peroxidation, and MDA levels while restoring the GSH. In addition, both HFD Stingmyo-KD rats and HFD rats with systematic inhibition by the STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury.
Innovation and Conclusion:
These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets and strategies for the treatment of lipotoxicity cardiomyopathy. Antioxid. Redox Signal. 42, 184–198.
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References
1.
BaiJ, CervantesC, LiuJ, et al.DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proc Natl Acad Sci U S A, 2017; 114(46):12196–12201; doi: 10.1073/pnas.1708744114
2.
CaiW, LiuL, ShiX, et al.Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis. Circulation, 2023; 147(19):1444–1460; doi: 10.1161/CIRCULATIONAHA.122.060257
3.
CalabreseV, CorneliusC, Dinkova-KostovaAT, et al.Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal, 2010 Dec 1;13(11):1763–1811; doi: 10.1089/ars.2009.3074
4.
ChenZ, JinZX, CaiJ, et al.Energy substrate metabolism and oxidative stress in metabolic cardiomyopathy. J Mol Med (Berl), 2022; 100(12):1721–1739; doi: 10.1007/s00109-022-02269-1
5.
ChenX, KangR, KroemerG, et al.Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol, 2021; 18(5):280–296; doi: 10.1038/s41571-020-00462-0
6.
ChenX, XuS, ZhaoC, et al.Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun, 2019; 516(1):37–43; doi: 10.1016/j.bbrc.2019.06.015
7.
Concetta ScutoM, MancusoC, TomaselloB, et al.Curcumin, Hormesis and the Nervous System. Nutrients, 2019; 11(10):2417; doi: 10.3390/nu11102417
8.
DaiC, KongB, QinT, et al.Inhibition of ferroptosis reduces susceptibility to frequent excessive alcohol consumption-induced atrial fibrillation. Toxicology, 2022; 465:153055; doi: 10.1016/j.tox.2021.153055
9.
EnginAB. What Is Lipotoxicity? Adv Exp Med Biol, 2017; 960:197–220; doi: 10.1007/978-3-319-48382-5_8
10.
FangX, ArdehaliH, MinJ, et al.The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol, 2023; 20(1):7–23; doi: 10.1038/s41569-022-00735-4
11.
FangX, WangH, HanD, et al.Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A, 2019; 116(7):2672–2680; doi: 10.1073/pnas.1821022116
12.
FerianiA, BizzarriM, TirM, et al.High-fat diet-induced aggravation of cardiovascular impairment in permethrin-treated Wistar rats. Ecotoxicol Environ Saf, 2021; 222:112461; doi: 10.1016/j.ecoenv.2021.112461
13.
ForoutanZ, ButlerAE, ZenginG, et al.Curcumin and Ferroptosis: A Promising Target for Disease Prevention and Treatment. Cell Biochem Biophys, 2024; doi: 10.1007/s12013-023-01212-6Jan 6
14.
GaoL, ZhangJ, YangT, et al.STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease. Mol Ther, 2023; 31(10):3084–3103; doi: 10.1016/j.ymthe.2023.07.026
15.
GarciaGJr, IrudayamJI, JeyachandranAV, et al.Innate immune pathway modulator screen identifies STING pathway activation as a strategy to inhibit multiple families of arbo and respiratory viruses. Cell Rep Med, 2023; 4(5):101024; doi: 10.1016/j.xcrm.2023.101024
16.
GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study. Lancet, 2017; 388(10053):1659–1724; doi: 10.1016/S0140-6736(16)31679-8
17.
GoldbergIJ, TrentCM, SchulzePC. Lipid metabolism and toxicity in the heart. Cell Metab, 2012; 15(6):805–812; doi: 10.1016/j.cmet.2012.04.006
18.
GongY, LiG, TaoJ, et al.Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism. Biochim Biophys Acta Mol Basis Dis, 2020; 1866(10):165855; doi: 10.1016/j.bbadis.2020.165855
19.
GongW, LuL, ZhouY, et al.The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction. Am J Physiol Renal Physiol, 2021; 320(4):F608–F616; doi: 10.1152/ajprenal.00554.2020
20.
HeLP, ZhouZX, LiCP. Narrative review of ferroptosis in obesity. J Cell Mol Med, 2023; 27(7):920–926; doi: 10.1111/jcmm.17701
21.
HsuCN, HsuanCF, LiaoD, et al.Anti-Diabetic therapy and heart failure: Recent advances in clinical evidence and molecular mechanism. Life (Basel), 2023; 13(4):1024; doi: 10.3390/life13041024
22.
HuH, ChenY, JingL, et al.The Link Between Ferroptosis and Cardiovascular Diseases: A Novel Target for Treatment. Front Cardiovasc Med, 2021; 8:710963; doi: 10.3389/fcvm.2021.710963
23.
JangS, Chapa-DubocqXR, TyurinaYY, et al.Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes. Redox Biol, 2021; 45(21):102021–102317; doi: 10.1016/j.redox.2021.10202110202100179-8;
24.
JiaM, QinD, ZhaoC, et al.Redox homeostasis maintained by GPX4 facilitates STING activation. Nat Immunol, 2020; 21(7):727–735; doi: 10.1038/s41590-020-0699-0
25.
JinL, YuB, WangH, et al.STING promotes ferroptosis through NCOA4-dependent ferritinophagy in acute kidney injury. Free Radic Biol Med, 2023; 208:348–360; doi: 10.1016/j.freeradbiomed.2023.08.025
26.
KobritzM, NofiC, SfakianosM, et al.Targeting sting to reduce sepsis-induced acute intestinal injury. Surgery, 2023 Oct;174(4):1071–1077; doi: 10.1016/j.surg.2023.06.032
27.
KongC, NiX, WangY, et al.ICA69 aggravates ferroptosis causing septic cardiac dysfunction via STING trafficking. Cell Death Discov, 2022; 8(1):187; doi: 10.1038/s41420-022-00957-yi
28.
LeeMMY, BrooksbankKJM, WetherallK, et al.Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation, 2021; 143(6):516–525; doi: 10.1161/CIRCULATIONAHA.120.052186
29.
LiJ, CaoF, YinHL, et al.Ferroptosis: Past, present and future. Cell Death Dis, 2020; 11(2):88; doi: 10.1038/s41419-020-2298-2
30.
LuoX, LiH, MaL, et al.Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology, 2018; 155(6):1971–1984.e4; doi: 10.1053/j.gastro.2018.09.010
31.
MaXM, GengK, LawBY, et al.Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes. Cell Biol Toxicol, 2023; 39(1):277–299; doi: 10.1007/s10565-021-09692-z
32.
Marín-RoyoG, Ortega-HernándezA, Martínez-MartínezE, et al.The Impact of Cardiac Lipotoxicity on Cardiac Function and Mirnas Signature in Obese and Non-Obese Rats with Myocardial Infarction. Sci Rep, 2019; 9(1):444; doi: 10.1038/s41598-018-36914-y
33.
MirandaJJ, Barrientos-GutiérrezT, CorvalanC, et al.Understanding the rise of cardiometabolic diseases in low- and middle-income countries. Nat Med, 2019; 25(11):1667–1679; doi: 10.1038/s41591-019-0644-7
34.
NakamuraM, SadoshimaJ. Cardiomyopathy in obesity, insulin resistance and diabetes. J Physiol, 2020; 598(14):2977–2993; doi: 10.1113/JP276747
35.
OduroPK, ZhengX, WeiJ, et al.The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B, 2022; 12(1):50–75; doi: 10.1016/j.apsb.2021.05.011
36.
OuM, JiangY, JiY, et al.Role and mechanism of ferroptosis in neurological diseases. Mol Metab, 2022; 61:101502; doi: 10.1016/j.molmet.2022.101502
37.
PalomequeJ, ChemalyER, ColosiP, et al.Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo. Gene Ther, 2007; 14(13):989–997; doi: 10.1038/sj.gt.3302895
38.
PeiZ, LiuY, LiuS, et al.FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis. Metabolism, 2021; 122:154840; doi: 10.1016/j.metabol.2021.154840i
39.
PetersonLR, JiangX, ChenL, et al.Alterations in plasma triglycerides and ceramides: Links with cardiac function in humans with type 2 diabetes. J Lipid Res, 2020; 61(7):1065–1074; doi: 10.1194/jlr.RA120000669
40.
QiY, WuZ, ChenD, et al.A role of STING signaling in obesity-induced lung inflammation. Int J Obes (Lond), 2023; 47(4):325–334; doi: 10.1038/s41366-023-01272-x
41.
RechL, RainerPP. The Innate Immune cGAS-STING-Pathway in Cardiovascular Diseases—A Mini Review. Front Cardiovasc Med, 2021; 8:715903; doi: 10.3389/fcvm.2021.715903
42.
ScarpelliniC, KlejborowskaG, LanthierC, et al.Beyond ferrostatin-1: A comprehensive review of ferroptosis inhibitors. Trends Pharmacol Sci, 2023; 44(12):902–916; doi: 10.1016/j.tips.2023.08.012
43.
ShaW, HuF, XiY, et al.Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus. J Diabetes Res, 2021; 2021:9999612; doi: 10.1155/2021/9999612
44.
ValenzuelaPL, Carrera-BastosP, Castillo-GarcíaA, et al.Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol, 2023; 20(7):475–494; doi: 10.1038/s41569-023-00847-5
45.
VilaIK, ChammaH, SteerA, et al.STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses. Cell Metab, 2022; 34(1):125–139.e8; doi: 10.1016/j.cmet.2021.12.007
46.
WangX, ChenX, ZhouW, et al.Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B, 2022; 12(2):708–722; doi: 10.1016/j.apsb.2021.10.005
47.
WangN, MaH, LiJ, et al.HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes. J Mol Cell Cardiol, 2021; 150:65–76; doi: 10.1016/j.yjmcc.2020.10.010
48.
WenZ, HeX, WangJ, et al.Hyperlipidemia induces proinflammatory responses by activating STING pathway through IRE1α-XBP1 in retinal endothelial cells. J Nutr Biochem, 2023; 112:109213; doi: 10.1016/j.jnutbio.2022.109213
49.
WuXY, ChenYJ, LiuCA, et al.STING Induces Liver Ischemia-Reperfusion Injury by Promoting Calcium-Dependent Caspase 1-GSDMD Processing in Macrophages. Oxid Med Cell Longev, 2022 Jan 30;2022:8123157; doi: 10.1155/2022/8123157
50.
XiongR, LiN, ChenL, et al.STING protects against cardiac dysfunction and remodelling by blocking autophagy. Cell Commun Signal, 2021; 19(1):109; doi: 10.1186/s12964-021-00793-0
51.
YangM, ZhaoL, GaoP, et al.DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity. EBioMedicine, 2019; 43:607–619; doi: 10.1016/j.ebiom.2019.04.044
52.
YuanL, MaoY, LuoW, et al.Palmitic acid dysregulates the Hippo-YAP pathway and inhibits angiogenesis by inducing mitochondrial damage and activating the cytosolic DNA sensor cGAS-STING-IRF3 signaling mechanism. J Biol Chem, 2017; 292(36):15002–15015; doi: 10.1074/jbc.M117.804005
53.
ZhangX, BaiXC, ChenZJ. Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity, 2020; 53(1):43–53; doi: 10.1016/j.immuni.2020.05.013
54.
ZhangS, KangL, DaiX, et al.Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase. Free Radic Biol Med, 2022; 193(Pt 1):202–212; doi: 10.1016/j.freeradbiomed.2022.10.004
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