Abstract
Inflammation is a pivotal feature of myocardial reperfusion–induced microvascular injury and dysfunction. However, the molecular mechanisms by which myocardial reperfusion triggered inflammation remain incurable. The NLRP3 inflammasome is a key intracellular sensor that detection of cellular stress to activation of caspase-1, and consequent IL-1β maturation and pyroptotic cell death. Here, we showed that NLRP3 inflammasome played a key role in myocardial reperfusion–induced microvascular injury. We observed NLRP3 inflammasome activation and pyroptosis in both cardiac microvascular endothelial cells and myocardial I/R animal model. Gastrodin, an effective monomeric component extracted from the herb Gastrodia elata BIume, blocked cardiac microvascular endothelial cell pyroptosis via inhibiting NLRP3/caspase-1 pathway. Gastrodin also reduced interleukin-1β (IL-1β) production in vivo and in vitro. Furthermore, gastrodin treatment attenuated infarct size and inflammatory cells infiltration and increased capillary formation. Gastrodin is thus a potential therapeutic for NLRP3-associated inflammatory disease.
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References
Akhtar-Schafer I et al (2018) Modulation of three key innate immune pathways for the most common retinal degenerative diseases [J]. EMBO Mol Med 10(10):1–27
Awad F, Assrawi E, Louvrier C, Jumeau C, Georgin-Lavialle S, Grateau G, Amselem S, Giurgea I, Karabina SA (2018) Inflammasome biology, molecular pathology and therapeutic implications[J]. Pharmacol Ther 187:133–149
Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, Ghosh A, Vella AT, Vanaja SK, Sarkar SN, Fitzgerald KA, Rathinam VAK (2018) Gasdermin D restrains type I interferon response to cytosolic DNA by disrupting ionic homeostasis [J]. Immunity. 49(3):413–426
Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling[J]. Nat Rev Immunol 16(7):407–420
Cocco M, Miglio G, Giorgis M, Garella D, Marini E, Costale A, Regazzoni L, Vistoli G, Orioli M, Massulaha-Ahmed R, Détraz-Durieux I, Groslambert M, Py BF, Bertinaria M (2016) Design, synthesis, and evaluation of acrylamide derivatives as direct NLRP3 inflammasome inhibitors [J]. ChemMedChem. 11(16):1790–1803
Coll RC, Robertson AAB, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KHG, Masters SL, Schroder K, Cooper MA, O'Neill LAJ (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases [J]. Nat Med 21(3):248–255
Davis BK, Wen H, Ting JPY (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases[J]. Annu Rev Immunol 29:707–735
de Torre-Minguela C et al (2017) The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases [J]. Front Immunol 8:43
Del Gobbo LC et al (2015) Contribution of major lifestyle risk factors for incident heart failure in older adults: the cardiovascular health study [J]. JACC Heart Fail 3(7):520–528
Feng S et al (2018) Mechanisms of gasdermin family members in inflammasome signaling and cell death [J]. J Mol Biol 430(18 Pt B):3068–3080
Fu S, Chen L, Wu Y, Tang Y, Tang L, Zhong Y, Wang S, Liu H, Wang X, Chen A (2018) Gastrodin pretreatment alleviates myocardial ischemia/reperfusion injury through promoting autophagic flux [J]. Biochem Biophys Res Commun 503(4):2421–2428
Fu Q et al (2018) NLRP3/caspase-1 pathway-induced pyroptosis mediated cognitive deficits in a mouse model of sepsis-associated encephalopathy [J]. Inflammation.
Gordon R, Albornoz EA (2018) Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice [J]. Sci Transl Med 10(465):1–12
He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, Liu Q, Liang G, Deng X, Jiang W, Zhou R (2018) Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity [J]. Nat Commun 9(1):2550–2562
Hong YJ, Jeong MH, Choi YH, Ko JS, Lee MG, Kang WY, Lee SE, Kim SH, Park KH, Sim DS, Yoon NS, Youn HJ, Kim KH, Park HW, Kim JH, Ahn Y, Cho JG, Park JC, Kang JC (2011) Impact of plaque components on no-reflow phenomenon after stent deployment in patients with acute coronary syndrome: a virtual histology-intravascular ultrasound analysis [J]. Eur Heart J 32(16):2059–2066
Kanneganti A, Malireddi RKS, Saavedra PHV, Vande Walle L, van Gorp H, Kambara H, Tillman H, Vogel P, Luo HR, Xavier RJ, Chi H, Lamkanfi M (2018) GSDMD is critical for autoinflammatory pathology in a mouse model of familial Mediterranean fever[J]. J Exp Med 215(6):1519–1529
Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S', Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury [J]. Circulation. 123(6):594–604
Kim HJ, Moon KD, Oh SY, Kim SP, Lee SR (2001) Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb, protects against kainic acid-induced neuronal damage in the mouse hippocampus [J]. Neurosci Lett 314(1–2):65–68
Kim HJ, Moon KD, Lee DS, Lee SH (2003) Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell death [J]. J Ethnopharmacol 84(1):95–98
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, Mayall JR, Ali MK, Starkey MR, Hansbro NG, Hirota JA, Wood LG, Simpson JL, Knight DA, Wark PA, Gibson PG, O’Neill LAJ, Cooper MA, Horvat JC, Hansbro PM (2017) Role for NLRP3 inflammasome-mediated, IL-1beta-dependent responses in severe, steroid-resistant asthma [J]. Am J Respir Crit Care Med 196(3):283–297
Li JJ et al (2018) Herbal compounds with special reference to gastrodin as potential therapeutic agents for microglia mediated neuroinflammation [J]. Curr Med Chem
Liu Y, Gao J, Peng M, Meng H, Ma H, Cai P, Xu Y, Zhao Q, Si G (2018) A review on central nervous system effects of gastrodin [J]. Front Pharmacol 9:24–46
Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KHG, Mok KH, Newsholme P, Nuñez G, Yodoi J, Kahn SE, Lavelle EC, O'Neill LAJ (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes [J]. Nat Immunol 11(10):897–904
McKenzie BA, Mamik MK, Saito LB, Boghozian R, Monaco MC, Major EO, Lu JQ, Branton WG, Power C (2018) Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis [J]. Proc Natl Acad Sci U S A 115(26):E6065–e6074
Mozaffarian D et al (2016) Executive summary: heart disease and stroke statistics--2016 update: a report from the American Heart Association [J]. Circulation. 133(4):447–454
Peng Z, Wang S, Chen G, cai M, Liu R, Deng J, Liu J, Zhang T, Tan Q, Hai C (2015) Gastrodin alleviates cerebral ischemic damage in mice by improving anti-oxidant and anti-inflammation activities and inhibiting apoptosis pathway [J]. Neurochem Res 40(4):661–673
Prochnicki T et al (2016) Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation [J]. F1000Res 5
Reed GW, Rossi JE, Cannon CP (2017) Acute myocardial infarction [J]. Lancet. 389(10065):197–210
Sadatomi D, Nakashioya K, Mamiya S, Honda S, Kameyama Y, Yamamura Y, Tanimura S, Takeda K (2017) Mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation [J]. J Biochem 161(6):503–512
Toldo S, Abbate A (2018) The NLRP3 inflammasome in acute myocardial infarction [J]. Nat Rev Cardiol 15(4):203–214
Toldo S, Mauro AG, Cutter Z, Abbate A (2018) Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury [J]. Am J Physiol Heart Circ Physiol 315:H1553–H1568
Wakabayashi T, Takahashi M, Yamamuro D, Karasawa T, Takei A, Takei S, Yamazaki H, Nagashima S, Ebihara K, Takahashi M, Ishibashi S (2018) Inflammasome activation aggravates cutaneous xanthomatosis and atherosclerosis in ACAT1 (acyl-CoA cholesterol acyltransferase 1) deficiency in bone marrow [J]. Arterioscler Thromb Vasc Biol 38(11):2576–2589
Yang P, Han Y, Gui L, Sun J, Chen YL, Song R, Guo JZ, Xie YN, Lu D, Sun L (2013) Gastrodin attenuation of the inflammatory response in H9c2 cardiomyocytes involves inhibition of NF-kappaB and MAPKs activation via the phosphatidylinositol 3-kinase signaling [J]. Biochem Pharmacol 85(8):1124–1133
Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T (2014) Inflammasome activation leads to caspase-1-dependent mitochondrial damage and block of mitophagy [J]. Proc Natl Acad Sci U S A 111(43):15514–15519
Funding
This work was supported in part by the National Natural Science Foundation of China (grant no. 31760292; grant no. 81760087; grant no. 81560050) and the Department of Science and Technology of Yunnan Province (grant no. 2017FA035; grant no. 2017FE467 (-008), Provincial major sepcial projects (grant no.2019ZF011-2) and the Program for Innovative Research Team (in Science and Technology) in the University of Yunnan Province.
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All animal experimental protocols were reviewed and approved by the Ethics Committee of Kunming Medical University for the use of laboratory animals.
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Sun, W., Lu, H., Lyu, L. et al. Gastrodin ameliorates microvascular reperfusion injury–induced pyroptosis by regulating the NLRP3/caspase-1 pathway. J Physiol Biochem 75, 531–547 (2019). https://doi.org/10.1007/s13105-019-00702-7
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DOI: https://doi.org/10.1007/s13105-019-00702-7