NLRP3 Inflammasome: Key Role in the Pathophysiology of Cardiac Disorders
and its Potential as a Therapeutic Target

Navneet      Arora; Ranjeet      Kumar

doi:10.2174/012210299X256054231020060356

Abstract

The NLRP3 inflammasome holds a pivotal position in the pathophysiological landscape of cardiac disorders, presenting itself as a promising therapeutic target. Central to this role are the proinflammatory cytokines Interleukin (IL)-1 and IL-18, which emerge as major players orchestrated by the activation of the NLRP3 inflammasome. This activation culminates in pyroptosis, a programmed form of cell death. While controlled activation of NLRP3 supports tissue repair, its excessive activation yields adverse consequences. Within the spectrum of cardiovascular diseases, ranging from abdominal aortic aneurysm to calcific aortic valve disease, the NLRP3 inflammasome is notably implicated. Atherosclerosis, myocardial infarction, diabetic cardiomyopathy, heart failure, and dilated cardiomyopathy collectively contribute to the genesis of inflammatory conditions. Key to this process is the nucleotide oligomerization domain-containing leucine-rich repeat protein 3 (NLRP3) inflammation, necessitating both priming and activation signals to orchestrate inflammation. Extensive scientific evidence substantiates the critical role of the NLRP3 inflammasome in cardiac disorders. Experimental models and clinical studies converge, highlighting its contribution to the intricate web of inflammatory pathways that underlie cardiac pathologies. This deeper understanding has spurred interest in targeting the NLRP3 inflammasome as a therapeutic avenue. Efforts to modulate the NLRP3 inflammasome are underway, aiming to temper its hyperactivity without disrupting its beneficial functions. Strategies involve small molecule inhibitors and biological agents, targeting various points along the signaling cascade. By selectively intervening in the NLRP3 pathway, researchers aspire to mitigate inflammatory responses, potentially ameliorating the progression of cardiac disorders. In conclusion, the NLRP3 inflammasome is a central orchestrator in the pathophysiology of diverse cardiac disorders. Its dual nature, capable of both driving repair and provoking harm, accentuates its significance as a therapeutic target. Scientific endeavors are actively unraveling its complexities, fostering the development of innovative interventions that could potentially revolutionize the management of cardiac inflammatory conditions.

[1]
Broz, P.; Dixit, V.M. Inflammasomes: Mechanism of assembly, regulation and signalling. Nat. Rev. Immunol.,  2016, 16(7), 407-420.
 [http://dx.doi.org/10.1038/nri.2016.58] [PMID: 27291964]

[2]
Martinon, F.; Burns, K.; Tschopp, J. The inflammasome. Mol. Cell,  2002, 10(2), 417-426.
 [http://dx.doi.org/10.1016/S1097-2765(02)00599-3] [PMID: 12191486]

[3]
Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B.G.; Fitzgerald, K.A.; Hornung, V.; Latz, E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol.,  2009, 183(2), 787-791.
 [http://dx.doi.org/10.4049/jimmunol.0901363] [PMID: 19570822]

[4]
Van Tassell, B.W.; Abbate, A. Interleukin-1 blockade in heart failure: Acute heart failure in myocardial infarction and chronic heart failure. Circ. Res.,  2013, 113(3), 254-267.
 [http://dx.doi.org/10.1161/CIRCRESAHA.113.300156]

[5]
Toldo, S.; Mezzaroma, E.; Mauro, A.G.; Salloum, F.; Van Tassell, B.W.; Abbate, A. The inflammasome in myocardial injury and cardiac remodeling. Antioxid. Redox Signal.,  2015, 22(13), 1146-1161.
 [http://dx.doi.org/10.1089/ars.2014.5989] [PMID: 25330141]

[6]
Lugrin, J.; Martinon, F.; Martinou, J.C. Inhibition of autophagy blocks the adaptive response to heat shock and oxidative stress in yeast. J. Biol. Chem.,  2010, 285(52), 41165-41175.
 [http://dx.doi.org/10.1074/jbc.M110.168036]

[7]
Hornung, V.; Bauernfeind, F.; Halle, A.; Samstad, E.O.; Kono, H.; Rock, K.L.; Fitzgerald, K.A.; Latz, E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol.,  2008, 9(8), 847-856.
 [http://dx.doi.org/10.1038/ni.1631] [PMID: 18604214]

[8]
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature,  2011, 469(7329), 221-225.
 [http://dx.doi.org/10.1038/nature09663] [PMID: 21124315]

[9]
Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.; Espevik, T.; Lien, E.; Fitzgerald, K.A.; Rock, K.L.; Moore, K.J.; Wright, S.D.; Hornung, V.; Latz, E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature,  2010, 464(7293), 1357-1361.
 [http://dx.doi.org/10.1038/nature08938] [PMID: 20428172]

[10]
Lamkanfi, M.; Dixit, V.M. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol.,  2009, 25, 393-417.
 [http://dx.doi.org/10.1146/annurev.cellbio.24.110707.175407] [PMID: 22974247]

[11]
Franchi, L.; Eigenbrod, T.; Muñoz-Planillo, R.; Nuñez, G. The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol.,  2009, 10(3), 241-247.
 [http://dx.doi.org/10.1038/ni.1703] [PMID: 19221555]

[12]
Latz, E.; Xiao, T.S.; Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol.,  2013, 13(6), 397-411.
 [http://dx.doi.org/10.1038/nri3452] [PMID: 23702978]

[13]
Tomasoni, D.; Adamo, M.; Lombardi, C.M.; Metra, M. Highlights in heart failure. ESC Heart Fail.,  2019, 6(6), 1105-1127.
 [http://dx.doi.org/10.1002/ehf2.12555] [PMID: 31997538]

[14]
Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr; Colvin, M.M.; Drazner, M.H.; Filippatos, G.S.; Fonarow, G.C.; Givertz, M.M.; Hollenberg, S.M.; Lindenfeld, J.; Masoudi, F.A.; McBride, P.E.; Peterson, P.N.; Stevenson, L.W.; Westlake, C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. J. Am. Coll. Cardiol.,  2017, 70(6), 776-803.
 [http://dx.doi.org/10.1016/j.jacc.2017.04.025] [PMID: 28461007]

[15]
Teneggi, V.; Sivakumar, N.; Chen, D.; Matter, A. Drugs’ development in acute heart failure: What went wrong? Heart Fail. Rev.,  2018, 23(5), 667-691.
 [http://dx.doi.org/10.1007/s10741-018-9707-y] [PMID: 29736812]

[16]
Schiattarella, G.G.; Sequeira, V.; Ameri, P. Distinctive patterns of inflammation across the heart failure syndrome. Heart Fail. Rev.,  2021, 26(6), 1333-1344.
 [http://dx.doi.org/10.1007/s10741-020-09949-5] [PMID: 32219614]

[17]
Murphy, S.P.; Kakkar, R.; McCarthy, C.P.; Januzzi, J.L., Jr Inflammation in heart failure. J. Am. Coll. Cardiol.,  2020, 75(11), 1324-1340.
 [http://dx.doi.org/10.1016/j.jacc.2020.01.014] [PMID: 32192660]

[18]
Mezzaroma, E.; Abbate, A.; Toldo, S. The inflammasome in heart failure. Curr. Opin. Physiol.,  2021, 19, 105-112.
 [http://dx.doi.org/10.1016/j.cophys.2020.09.013] [PMID: 34917871]

[19]
Toldo, S.; Abbate, A. The NLRP3 inflammasome in acute myocardial infarction. Nat. Rev. Cardiol.,  2018, 15(4), 203-214.
 [http://dx.doi.org/10.1038/nrcardio.2017.161] [PMID: 29143812]

[20]
Abbate, A.; Toldo, S.; Marchetti, C.; Kron, J.; Van Tassell, B.W.; Dinarello, C.A. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ. Res.,  2020, 126(9), 1260-1280.
 [http://dx.doi.org/10.1161/CIRCRESAHA.120.315937] [PMID: 32324502]

[21]
Silvis, M.J.M.; Demkes, E.J.; Fiolet, A.T.L.; Dekker, M.; Bosch, L.; van Hout, G.P.J.; Timmers, L.; de Kleijn, D.P.V. Immunomodulation of the NLRP3 inflammasome in atherosclerosis, coronary artery disease, and acute myocardial infarction. J. Cardiovasc. Transl. Res.,  2021, 14(1), 23-34.
 [http://dx.doi.org/10.1007/s12265-020-10049-w] [PMID: 32648087]

[22]
Sandanger, Ø.; Ranheim, T.; Vinge, L.E.; Bliksøen, M.; Alfsnes, K.; Finsen, A.V.; Dahl, C.P.; Askevold, E.T.; Florholmen, G.; Christensen, G.; Fitzgerald, K.A.; Lien, E.; Valen, G.; Espevik, T.; Aukrust, P.; Yndestad, A. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury. Cardiovasc. Res.,  2013, 99(1), 164-174.
 [http://dx.doi.org/10.1093/cvr/cvt091] [PMID: 23580606]

[23]
Heijman, J.; Muna, A.P.; Veleva, T.; Molina, C.E.; Sutanto, H.; Tekook, M.; Wang, Q.; Abu-Taha, I.H.; Gorka, M.; Künzel, S.; El-Armouche, A.; Reichenspurner, H.; Kamler, M.; Nikolaev, V.; Ravens, U.; Li, N.; Nattel, S.; Wehrens, X.H.T.; Dobrev, D. Atrial myocyte NLRP3/CaMKII nexus forms a substrate for postoperative atrial fibrillation. Circ. Res.,  2020, 127(8), 1036-1055.
 [http://dx.doi.org/10.1161/CIRCRESAHA.120.316710] [PMID: 32762493]

[24]
Mehta, S.; Vijayvergiya, R.; Dhawan, V. Activation of NLRP3 inflammasome assembly is associated with smoking status of patients with coronary artery disease. Int. Immunopharmacol.,  2020, 87, 106820.
 [http://dx.doi.org/10.1016/j.intimp.2020.106820] [PMID: 32711374]

[25]
Yao, C.; Veleva, T.; Scott, L., Jr; Cao, S.; Li, L.; Chen, G.; Jeyabal, P.; Pan, X.; Alsina, K.M.; Abu-Taha, I.; Ghezelbash, S.; Reynolds, C.L.; Shen, Y.H.; LeMaire, S.A.; Schmitz, W.; Müller, F.U.; El-Armouche, A.; Tony Eissa, N.; Beeton, C.; Nattel, S.; Wehrens, X.H.T.; Dobrev, D.; Li, N. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation,  2018, 138(20), 2227-2242.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035202] [PMID: 29802206]

[26]
Rajamäki, K.; Lappalainen, J.; Öörni, K.; Välimäki, E.; Matikainen, S.; Kovanen, P.T.; Eklund, K.K. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: A novel link between cholesterol metabolism and inflammation. PLoS One,  2010, 5(7), e11765.
 [http://dx.doi.org/10.1371/journal.pone.0011765] [PMID: 20668705]

[27]
Ahlehoff, O.; Gislason, G.H.; Jørgensen, C.H.; Lindhardsen, J.; Charlot, M.; Olesen, J.B.; Abildstrøm, S.Z.; Skov, L.; Torp-Pedersen, C.; Hansen, P.R. Psoriasis and risk of atrial fibrillation and ischaemic stroke: A Danish Nationwide Cohort Study. Eur. Heart J.,  2012, 33(16), 2054-2064.
 [http://dx.doi.org/10.1093/eurheartj/ehr285] [PMID: 21840930]

[28]
Kristensen, S.L.; Lindhardsen, J.; Ahlehoff, O.; Erichsen, R.; Lamberts, M.; Khalid, U.; Torp-Pedersen, C.; Nielsen, O.H.; Gislason, G.H.; Hansen, P.R. Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: A nationwide study. Europace,  2014, 16(4), 477-484.
 [http://dx.doi.org/10.1093/europace/eut312] [PMID: 24108228]

[29]
Koyfman, L.; Brotfain, E.; Kutz, R.; Frenkel, A.; Schwartz, A.; Boniel, A.; Zlotnik, A.; Klein, M. Epidemiology of new-onset paroxysmal atrial fibrillation in the General Intensive Care Unit population and after discharge from ICU. A retrospective epidemiological study. Anestezjol. Intens. Ter.,  2015, 47(4), 309-314.
 [http://dx.doi.org/10.5603/AIT.a2015.0040] [PMID: 26210522]

[30]
Walkey, A.J.; Wiener, R.S.; Ghobrial, J.M.; Curtis, L.H.; Benjamin, E.J. Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA,  2011, 306(20), 2248-2254.
 [http://dx.doi.org/10.1001/jama.2011.1615] [PMID: 22081378]

[31]
Walkey, A.J.; Greiner, M.A.; Heckbert, S.R.; Jensen, P.N.; Piccini, J.P.; Sinner, M.F.; Curtis, L.H.; Benjamin, E.J. Atrial fibrillation among Medicare beneficiaries hospitalized with sepsis: Incidence and risk factors. Am. Heart J.,  2013, 165(6), 949-955.e3.
 [http://dx.doi.org/10.1016/j.ahj.2013.03.020] [PMID: 23708166]

[32]
Coll, R.C.; Hill, J.R.; Day, C.J.; Zamoshnikova, A.; Boucher, D.; Massey, N.L.; Chitty, J.L.; Fraser, J.A.; Jennings, M.P.; Robertson, A.A.B.; Schroder, K. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol.,  2019, 15(6), 556-559.
 [http://dx.doi.org/10.1038/s41589-019-0277-7] [PMID: 31086327]

[33]
Marchetti, C.; Swartzwelter, B.; Gamboni, F.; Neff, C.P.; Richter, K.; Azam, T.; Carta, S.; Tengesdal, I.; Nemkov, T.; D’Alessandro, A.; Henry, C.; Jones, G.S.; Goodrich, S.A.; St Laurent, J.P.; Jones, T.M.; Scribner, C.L.; Barrow, R.B.; Altman, R.D.; Skouras, D.B.; Gattorno, M.; Grau, V.; Janciauskiene, S.; Rubartelli, A.; Joosten, L.A.B.; Dinarello, C.A. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl. Acad. Sci.,  2018, 115(7), E1530-E1539.
 [http://dx.doi.org/10.1073/pnas.1716095115] [PMID: 29378952]

[34]
Ge, C.; Cheng, Y.; Fan, Y.; He, Y. Vincristine attenuates cardiac fibrosis through the inhibition of NLRP3 inflammasome activation. Clin. Sci.,  2021, 135(11), 1409-1426.
 [http://dx.doi.org/10.1042/CS20210189] [PMID: 33977303]

[35]
Nie, C.; Ding, X.; A, R.; Zheng, M.; Li, Z.; Pan, S.; Yang, W. Hydrogen gas inhalation alleviates myocardial ischemia-reperfusion injury by the inhibition of oxidative stress and NLRP3-mediated pyroptosis in rats. Life Sci.,  2021, 272, 119248.
 [http://dx.doi.org/10.1016/j.lfs.2021.119248] [PMID: 33621592]

[36]
Chen, S.; Wang, Y.; Pan, Y.; Liu, Y.; Zheng, S.; Ding, K.; Mu, K.; Yuan, Y.; Li, Z.; Song, H.; Jin, Y.; Fu, J. Novel role for tranilast in regulating NLRP3 ubiquitination, vascular inflammation, and atherosclerosis. J. Am. Heart Assoc.,  2020, 9(12), e015513.
 [http://dx.doi.org/10.1161/JAHA.119.015513] [PMID: 32476536]

[37]
He, Y.; Varadarajan, S.; Muñoz-Planillo, R.; Burberry, A.; Nakamura, Y.; Núñez, G. 3,4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J. Biol. Chem.,  2014, 289(2), 1142-1150.
 [http://dx.doi.org/10.1074/jbc.M113.515080] [PMID: 24265316]

[38]
a) Dinarello, C. A.; Simon, A.; van der Meer, J. W. M. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Reviews Drug Discovery,  2012, 11(8), 633-652.
 [http://dx.doi.org/10.1038/nrd3800]; 
b) Kuipers, S.; Klein Klouwenberg, PM.; Cremer, OL. Incidence, risk factors and outcomes of new-onset atrial fibrillation in patients with sepsis: A systematic review. Crit Care.,  2014, 18(6), 688.
 [http://dx.doi.org/10.1186/s13054-014-0688-5]

[39]
Xu, Y.; Xue, Y.; Wang, Y.; Feng, D.; Lin, S.; Xu, L. Multiple-modulation effects of Oridonin on the production of proinflammatory cytokines and neurotrophic factors in LPS-activated microglia. Int. Immunopharmacol.,  2009, 9(3), 360-365.
 [http://dx.doi.org/10.1016/j.intimp.2009.01.002] [PMID: 19185062]

[40]
Wei, Z.; Fei, Y.; Wang, Q. Oridonin attenuates cardiac fibrosis by regulating the TGF-β/Smad signaling pathway via inhibition of the NALP3 inflammasome. Mol. Med. Rep.,  2021, 24(1), 201.
 [http://dx.doi.org/10.3892/mmr.2021.12165] [PMID: 34080650]

[41]
Jo, E.K.; Kim, J.K.; Shin, D.M.; Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell. Mol. Immunol.,  2016, 13(2), 148-159.
 [http://dx.doi.org/10.1038/cmi.2015.95] [PMID: 26549800]

[42]
Tong, Y.; Wang, Z.; Cai, L.; Lin, L.; Liu, J.; Cheng, J. NLRP3 Inflammasome and Its Central Role in the Cardiovascular Diseases. Oxid. Med. Cell. Longev.,  2020, 2020, 1-8.
 [http://dx.doi.org/10.1155/2020/4293206] [PMID: 32377298]

[43]
Dobrev, D.; Heijman, J.; Hiram, R.; Li, N.; Nattel, S. Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology. Nat. Rev. Cardiol.,  2023, 20(3), 145-167.
 [http://dx.doi.org/10.1038/s41569-022-00759-w] [PMID: 36109633]

[44]
Serhan, C.N.; Gupta, S.K.; Perretti, M.; Godson, C.; Brennan, E.; Li, Y.; Soehnlein, O.; Shimizu, T.; Werz, O.; Chiurchiù, V.; Azzi, A.; Dubourdeau, M.; Gupta, S.S.; Schopohl, P.; Hoch, M.; Gjorgevikj, D.; Khan, F.M.; Brauer, D.; Tripathi, A.; Cesnulevicius, K.; Lescheid, D.; Schultz, M.; Särndahl, E.; Repsilber, D.; Kruse, R.; Sala, A.; Haeggström, J.Z.; Levy, B.D.; Filep, J.G.; Wolkenhauer, O. The Atlas of Inflammation Resolution (AIR). Mol. Aspects Med.,  2020, 74, 100894.
 [http://dx.doi.org/10.1016/j.mam.2020.100894] [PMID: 32893032]

[45]
Mastrocola, R.; Penna, C.; Tullio, F.; Femminò, S.; Nigro, D.; Chiazza, F.; Serpe, L.; Collotta, D.; Alloatti, G.; Cocco, M.; Bertinaria, M.; Pagliaro, P.; Aragno, M.; Collino, M. Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways. Oxid. Med. Cell. Longev.,  2016, 2016, 1-11.
 [http://dx.doi.org/10.1155/2016/5271251] [PMID: 28053692]

[46]
Juliana, C.; Fernandes-Alnemri, T.; Wu, J.; Datta, P.; Solorzano, L.; Yu, J.W.; Meng, R.; Quong, A.A.; Latz, E.; Scott, C.P.; Alnemri, E.S. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J. Biol. Chem.,  2010, 285(13), 9792-9802.
 [http://dx.doi.org/10.1074/jbc.M109.082305] [PMID: 20093358]

[47]
Wu, D.; Chen, Y.; Sun, Y.; Gao, Q.; Li, H.; Yang, Z.; Wang, Y.; Jiang, X.; Yu, B. Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review. Inflammation,  2020, 43(1), 17-23.
 [http://dx.doi.org/10.1007/s10753-019-01098-8] [PMID: 31646445]

[48]
Fan, Y Retracted: CY-09 inhibits NLRP3 inflammasome activation to relieve pain via TRPA1. Comput Math Methods Med,  2021, 2023, 9759851.
 [http://dx.doi.org/10.1155/2021/9806690]

[49]
He, H.; Jiang, H.; Chen, Y.; Ye, J.; Wang, A.; Wang, C.; Liu, Q.; Liang, G.; Deng, X.; Jiang, W.; Zhou, R. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat. Commun.,  2018, 9(1), 2550.
 [http://dx.doi.org/10.1038/s41467-018-04947-6] [PMID: 29959312]

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DOI https://dx.doi.org/10.2174/012210299X256054231020060356	Print ISSN 2210-299X
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NLRP3 Inflammasome: Key Role in the Pathophysiology of Cardiac Disorders and its Potential as a Therapeutic Target

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