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Stimulator of interferon genes (STING) has recently been found to play a crucial role in cardiac sterile inflammation and dysfunction. The role of stimulator of interferon genes (STING) in cardiac sterile inflammation and dysfunction has been recently discovered. This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway. To investigate this, transverse aortic constriction (TAC) was performed on STING knockout mice to induce pressure overload-induced cardiac remodeling. Subsequently, cardiac function, remodeling, and inflammation levels were evaluated. The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin Ⅱ (Ang Ⅱ)-stimulated cardiac fibroblasts. Loss of STING expression led to a significant reduction in inflammatory responses, mitochondrial fragmentation, and oxidative stress in the heart, resulting in attenuated cardiac remodeling and dysfunction. Furthermore, the exacerbation of pressure overload-induced STING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was suppressed through the silencing of Parkin, an E3 ubiquitin ligase. Taken together, these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation. Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.
Kim GH, Uriel N, Burkhoff D. Reverse remodelling and myocardial recovery in heart failure. Nat Rev Cardiol. 2018;15(2):83-96.
Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118(6):1021-1040.
Bacmeister L, Schwarzl M, Warnke S, et al. Inflammation and fibrosis in murine models of heart failure. Basic Res Cardiol. 2019;114(3):19.
Zhang Y, Bauersachs J, Langer HF. Immune mechanisms in heart failure. Eur J Heart Fail. 2017;19(11):1379-1389.
King KR, Aguirre AD, Ye YX, et al. IRF3 and type Ⅰ interferons fuel a fatal response to myocardial infarction. Nat Med. 2017;23(12):1481-1487.
Peng Y, Zhou G, Guo M, Cheng Z, Luo S, Guo Y. Inhibition of Stimulator of interferon genes protects against myocardial ischemia-reperfusion injury in diabetic mice. Cardiovasc Innov Appl. 2023;8(1).
Cao DJ, Schiattarella GG, Villalobos E, et al. Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation. 2018;137(24):2613-2634.
Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016;17(10):1142-1149.
Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type Ⅰ interferon pathway. Science. 2013;339(6121):786-791.
Nakayama H, Otsu K. Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. Biochem J. 2018;475(5):839-852.
Meyer A, Laverny G, Bernardi L, et al. Mitochondria: an organelle of bacterial origin controlling inflammation. Front Immunol. 2018;9:536.
Nie S, Lu J, Wang L, Gao M. Pro-inflammatory role of cell-free mitochondrial DNA in cardiovascular diseases. IUBMB Life. 2020;72(9):1879-1890.
Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020;21(4):e49799.
Oka T, Hikoso S, Yamaguchi O, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 2012;485(7397):251-255.
Bai J, Cervantes C, Liu J, 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.
Guo Y, Wang Z, Qin X, et al. Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart. Cardiovasc Res. 2018;114(7):979-991.
Wai T, García-Prieto J, Baker MJ, et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015;350(6265):aad0116.
Shires SE, Gustafsson ÅB. Mitophagy and heart failure. J Mol Med. 2015;93(3):253-262.
Vásquez-Trincado C, García-Carvajal I, Pennanen C, et al. Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol. 2016;594(3):509-525.
Wang B, Nie J, Wu L, et al. AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. Circ Res. 2018;122(5):712-729.
Lin Q, Li S, Jiang N, et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 2019;26:101254.
Zhuang X, Ma J, Xu G, Sun Z. SHP-1 knockdown suppresses mitochondrial biogenesis and aggravates mitochondria-dependent apoptosis induced by all trans retinal through the STING/AMPK pathways. Mol Med. 2022;28(1):125.
Gong W, Lu L, Zhou Y, et al. The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction. Am J Physiol Ren Physiol. 2021;320(4):F608-F616.
Shinde AV, Frangogiannis NG. Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol. 2014;70:74-82.
Billia F, Hauck L, Konecny F, Rao V, Shen J, Mak TW. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc Natl Acad Sci U S A. 2011;108(23):9572-9577.
White MJ, McArthur K, Metcalf D, et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type Ⅰ IFN production. Cell. 2014;159(7):1549-1562.
Cartledge JE, Kane C, Dias P, et al. Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators. Cardiovasc Res. 2015;105(3):260-270.
Piccoli MT, Gupta SK, Viereck J, et al. Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res. 2017;121(5):575-583.
Cheng Z, Qi M, Zhang C, Mao Y. Myocardial fibrosis in the pathogenesis, diagnosis, and treatment of hypertrophic cardiomyopathy. Cardiovasc Innov Appl. 2021;5(4):267-274.
van Linthout S, Miteva K, Tschöpe C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res. 2014;102(2):258-269.
Kawaguchi M, Takahashi M, Hata T, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123(6):594-604.
Luo W, Wang Y, Zhang L, et al. Critical role of cytosolic DNA and its sensing adaptor STING in aortic degeneration, dissection, and rupture. Circulation. 2020;141(1):42-66.
Mao Y, Luo W, Zhang L, et al. STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2017;37(5):920-929.
Hu D, Cui YX, Wu MY, et al. Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure. Am J Physiol Heart Circ Physiol. 2020;318(6):H1525-H1537.
Zhang Y, Chen W, Wang Y. STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress. Biomed Pharmacother. 2020;125:110022.
Xiong R, Li N, Chen L, et al. STING protects against cardiac dysfunction and remodelling by blocking autophagy. Cell Commun Signal. 2021;19(1):109.
Purnomo Y, Piccart Y, Coenen T, Prihadi JS, Lijnen PJ. Oxidative stress and transforming growth factor-β1-induced cardiac fibrosis. Cardiovasc Hematol Disord: Drug Targets. 2013;13(2):165-172.
Zhao QD, Viswanadhapalli S, Williams P, et al. NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation. 2015;131(7):643-655.
Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 2019;24(8):1583.
Chung KW, Dhillon P, Huang S, et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metabol. 2019;30(4):784-799.e5.
Zhang JZ, Liu Z, Liu J, Ren JX, Sun TS. Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue. Int J Mol Med. 2014;33(4):817-824.
Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):R170-R185.
Harris J, Deen N, Zamani S, Hasnat MA. Mitophagy and the release of inflammatory cytokines. Mitochondrion. 2018;41:2-8.
Sliter DA, Martinez J, Hao L, et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018;561(7722):258-262.
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