Abstract
During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a multifunctional protease that cleaves both extracellular and intracellular proteins. Oxidative stress also impairs mitochondrial function which is regulated by different proteins, including mitofusin-2 (Mfn-2), which is lost in IR injury. Oxidative stress and mitochondrial dysfunction trigger the NLRP3 inflammasome and the innate immune response which invokes the de novo expression of an N-terminal truncated isoform of MMP-2 (NTT-MMP-2) at or near mitochondria. We hypothesized that MMP-2 proteolyzes Mfn-2 during myocardial IR injury, impairing mitochondrial function and enhancing the inflammasome response. Isolated hearts from mice subjected to IR injury (30 min ischemia/40 min reperfusion) showed a significant reduction in left ventricular developed pressure (LVDP) compared to aerobically perfused hearts. IR injury increased MMP-2 activity as observed by gelatin zymography and increased degradation of troponin I, an intracellular MMP-2 target. MMP-2 preferring inhibitors, ARP-100 or ONO-4817, improved post-ischemic recovery of LVDP compared to vehicle perfused IR hearts. In muscle fibers isolated from IR hearts the rates of mitochondrial oxygen consumption and ATP production were impaired compared to those from aerobic hearts, whereas ARP-100 or ONO-4817 attenuated these reductions. IR hearts showed higher levels of NLRP3, cleaved caspase-1 and interleukin-1β in the cytosolic fraction, while the mitochondria-enriched fraction showed reduced levels of Mfn-2, compared to aerobic hearts. ARP-100 or ONO-4817 attenuated these changes. Co-immunoprecipitation showed that MMP-2 is associated with Mfn-2 in aerobic and IR hearts. ARP-100 or ONO-4817 also reduced infarct size and cell death in hearts subjected to 45 min ischemia/120 min reperfusion. Following myocardial IR injury, impaired contractile function and mitochondrial respiration and elevated inflammasome response could be attributed, at least in part, to MMP-2 activation, which targets and cleaves mitochondrial Mfn-2. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in IR injury in part by preserving Mfn-2 and suppressing inflammation.
Similar content being viewed by others
Data availability
The data underlying this article is available in the article and in its online supplementary material.
References
Adebayo M, Singh S, Singh AP, Dasgupta S (2021) Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis. Faseb J 35:e21620. https://doi.org/10.1096/fj.202100067R
Ainbinder A, Boncompagni S, Protasi F, Dirksen RT (2015) Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle. Cell Calcium 57:14–24. https://doi.org/10.1016/j.ceca.2014.11.002
Ali MA, Cho WJ, Hudson B, Kassiri Z, Granzier H, Schulz R (2010) Titin is a target of matrix metalloproteinase-2: implications in myocardial ischemia/reperfusion injury. Circulation 122:2039–2047. https://doi.org/10.1161/circulationaha.109.930222
Ali MA, Chow AK, Kandasamy AD, Fan X, West LJ, Crawford BD, Simmen T, Schulz R (2012) Mechanisms of cytosolic targeting of matrix metalloproteinase-2. J Cell Physiol 227:3397–3404. https://doi.org/10.1002/jcp.24040
Ali MA, Stepanko A, Fan X, Holt A, Schulz R (2012) Calpain inhibitors exhibit matrix metalloproteinase-2 inhibitory activity. Biochem Biophys Res Commun 423:1–5. https://doi.org/10.1016/j.bbrc.2012.05.005
Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P (2002) Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection. Circ Res 90:390–397. https://doi.org/10.1161/01.res.0000012702.90501.8d
Bencsik P, Pálóczi J, Kocsis GF, Pipis J, Belecz I, Varga ZV, Csonka C, Görbe A, Csont T, Ferdinandy P (2014) Moderate inhibition of myocardial matrix metalloproteinase-2 by ilomastat is cardioprotective. Pharmacol Res 80:36–42. https://doi.org/10.1016/j.phrs.2013.12.007
Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Burkhardt K, Feng Z, Gilliland GL, Iype L, Jain S, Fagan P, Marvin J, Padilla D, Ravichandran V, Schneider B, Thanki N, Weissig H, Westbrook JD, Zardecki C (2002) The protein data bank. Acta Crystallogr D Biol Crystallogr 58:899–907. https://doi.org/10.1107/s0907444902003451
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Gallo Cassarino T, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252-258. https://doi.org/10.1093/nar/gku340
Bøtker HE, Cabrera-Fuentes HA, Ruiz-Meana M, Heusch G, Ovize M (2020) Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST-segment elevation myocardial infarction. J Cell Mol Med 24:2717–2729. https://doi.org/10.1111/jcmm.14953
Bräuninger H, Krüger S, Bacmeister L, Nyström A, Eyerich K, Westermann D, Lindner D (2023) Matrix metalloproteinases in coronary artery disease and myocardial infarction. Basic Res Cardiol 118:18. https://doi.org/10.1007/s00395-023-00987-2
Braunwald E, Kloner RA (1985) Myocardial reperfusion: a double-edged sword? J Clin Invest 76:1713–1719. https://doi.org/10.1172/jci112160
Cadete VJ, Arcand SA, Chaharyn BM, Doroszko A, Sawicka J, Mousseau DD, Sawicki G (2013) Matrix metalloproteinase-2 is activated during ischemia/reperfusion in a model of myocardial infarction. Can J Cardiol 29:1495–1503. https://doi.org/10.1016/j.cjca.2013.03.014
Chan BYH, Roczkowsky A, Cho WJ, Poirier M, Sergi C, Keschrumrus V, Churko JM, Granzier H, Schulz R (2021) MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling. Cardiovasc Res 117:188–200. https://doi.org/10.1093/cvr/cvaa017
Chan BYH, Roczkowsky A, Moser N, Poirier M, Hughes BG, Ilarraza R, Schulz R (2018) Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes. Can J Physiol Pharmacol 96:1238–1245. https://doi.org/10.1139/cjpp-2018-0275
Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 276:30724–30728. https://doi.org/10.1074/jbc.M103701200
Chen Q, Paillard M, Gomez L, Ross T, Hu Y, Xu A, Lesnefsky EJ (2011) Activation of mitochondrial μ-calpain increases AIF cleavage in cardiac mitochondria during ischemia-reperfusion. Biochem Biophys Res Commun 415:533–538. https://doi.org/10.1016/j.bbrc.2011.10.037
Chen Q, Thompson J, Hu Y, Dean J, Lesnefsky EJ (2019) Inhibition of the ubiquitous calpains protects complex I activity and enables improved mitophagy in the heart following ischemia-reperfusion. Am J Physiol Cell Physiol 317:C910-921. https://doi.org/10.1152/ajpcell.00190.2019
Chen Y, Csordás G, Jowdy C, Schneider TG, Csordás N, Wang W, Liu Y, Kohlhaas M, Meiser M, Bergem S, Nerbonne JM, Dorn GW 2nd, Maack C (2012) Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk. Circ Res 111:863–875. https://doi.org/10.1161/circresaha.112.266585
Chen Y, Liu Y, Dorn GW 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109:1327–1331. https://doi.org/10.1161/circresaha.111.258723
Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101:1833–1839. https://doi.org/10.1161/01.cir.101.15.1833
Davidson SM, Ferdinandy P, Andreadou I, Bøtker HE, Heusch G, Ibáñez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, Garcia-Dorado D (2019) Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol 73:89–99. https://doi.org/10.1016/j.jacc.2018.09.086
de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. https://doi.org/10.1038/nature07534
DeLeon-Pennell KY, Meschiari CA, Jung M, Lindsey ML (2017) Matrix metalloproteinases in myocardial infarction and heart failure. Prog Mol Biol Transl Sci 147:75–100. https://doi.org/10.1016/bs.pmbts.2017.02.001
Disatnik MH, Ferreira JC, Campos JC, Gomes KS, Dourado PM, Qi X, Mochly-Rosen D (2013) Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction. J Am Heart Assoc 2:e000461. https://doi.org/10.1161/jaha.113.000461
Dong G, Chen T, Ren X, Zhang Z, Huang W, Liu L, Luo P, Zhou H (2016) Rg1 prevents myocardial hypoxia/reoxygenation injury by regulating mitochondrial dynamics imbalance via modulation of glutamate dehydrogenase and mitofusin 2. Mitochondrion 26:7–18. https://doi.org/10.1016/j.mito.2015.11.003
Eckhard U, Huesgen PF, Schilling O, Bellac CL, Butler GS, Cox JH, Dufour A, Goebeler V, Kappelhoff R, Keller UAD, Klein T, Lange PF, Marino G, Morrison CJ, Prudova A, Rodriguez D, Starr AE, Wang Y, Overall CM (2016) Active site specificity profiling of the matrix metalloproteinase family: proteomic identification of 4300 cleavage sites by nine MMPs explored with structural and synthetic peptide cleavage analyses. Matrix Biol 49:37–60. https://doi.org/10.1016/j.matbio.2015.09.003
Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362. https://doi.org/10.1126/science.1207385
Gao CQ, Sawicki G, Suarez-Pinzon WL, Csont T, Wozniak M, Ferdinandy P, Schulz R (2003) Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction. Cardiovasc Res 57:426–433. https://doi.org/10.1016/s0008-6363(02)00719-8
Givvimani S, Pushpakumar S, Veeranki S, Tyagi SC (2014) Dysregulation of Mfn2 and Drp-1 proteins in heart failure. Can J Physiol Pharmacol 92:583–591. https://doi.org/10.1139/cjpp-2014-0060
Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM, Garcia-Dorado D (2017) Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 38:935–941. https://doi.org/10.1093/eurheartj/ehw145
Hom J, Sheu SS (2009) Morphological dynamics of mitochondria–a special emphasis on cardiac muscle cells. J Mol Cell Cardiol 46:811–820. https://doi.org/10.1016/j.yjmcc.2009.02.023
Hom J, Yu T, Yoon Y, Porter G, Sheu SS (2010) Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 1797:913–921. https://doi.org/10.1016/j.bbabio.2010.03.018
Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6:480–498. https://doi.org/10.1038/nrd2308
Hughes BG, Fan X, Cho WJ, Schulz R (2014) MMP-2 is localized to the mitochondria-associated membrane of the heart. Am J Physiol Heart Circ Physiol 306:H764-770. https://doi.org/10.1152/ajpheart.00909.2013
Hughes BG, Schulz R (2014) Targeting MMP-2 to treat ischemic heart injury. Basic Res Cardiol 109:424. https://doi.org/10.1007/s00395-014-0424-y
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589. https://doi.org/10.1038/s41586-021-03819-2
Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236. https://doi.org/10.1038/nature04517
Kuznetsov AV, Veksler V, Gellerich FN, Saks V, Margreiter R, Kunz WS (2008) Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells. Nat Protoc 3:965–976. https://doi.org/10.1038/nprot.2008.61
Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411. https://doi.org/10.1038/nri3452
Li F, Leier A, Liu Q, Wang Y, Xiang D, Akutsu T, Webb GI, Smith AI, Marquez-Lago T, Li J, Song J (2020) Procleave: predicting protease-specific substrate cleavage sites by combining sequence and structural information. Genom Proteom Bioinf 18:52–64. https://doi.org/10.1016/j.gpb.2019.08.002
Liu Q, Zhang D, Hu D, Zhou X, Zhou Y (2018) The role of mitochondria in NLRP3 inflammasome activation. Mol Immunol 103:115–124. https://doi.org/10.1016/j.molimm.2018.09.010
Liu W, Zhang X, Zhao M, Zhang X, Chi J, Liu Y, Lin F, Fu Y, Ma D, Yin X (2015) Activation in M1 but not M2 macrophages contributes to cardiac remodeling after myocardial infarction in rats: a critical role of the calcium sensing receptor/NRLP3 inflammasome. Cell Physiol Biochem 35:2483–2500. https://doi.org/10.1159/000374048
Liu X, Li M, Chen Z, Yu Y, Shi H, Yu Y, Wang Y, Chen R, Ge J (2022) Mitochondrial calpain-1 activates NLRP3 inflammasome by cleaving ATP5A1 and inducing mitochondrial ROS in CVB3-induced myocarditis. Basic Res Cardiol 117:40. https://doi.org/10.1007/s00395-022-00948-1
Lovett DH, Chu C, Wang G, Ratcliffe MB, Baker AJ (2014) A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium. Front Physiol 5:363. https://doi.org/10.3389/fphys.2014.00363
Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS (2012) A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One 7:e34177. https://doi.org/10.1371/journal.pone.0034177
Lovett DH, Mahimkar R, Raffai RL, Cape L, Zhu BQ, Jin ZQ, Baker AJ, Karliner JS (2013) N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure. PLoS One 8:e68154. https://doi.org/10.1371/journal.pone.0068154
Maneechote C, Palee S, Chattipakorn SC, Chattipakorn N (2017) Roles of mitochondrial dynamics modulators in cardiac ischaemia/reperfusion injury. J Cell Mol Med 21:2643–2653. https://doi.org/10.1111/jcmm.13330
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232. https://doi.org/10.1038/nature04515
Mourier A, Motori E, Brandt T, Lagouge M, Atanassov I, Galinier A, Rappl G, Brodesser S, Hultenby K, Dieterich C, Larsson NG (2015) Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J Cell Biol 208:429–442. https://doi.org/10.1083/jcb.201411100
Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88:581–609. https://doi.org/10.1152/physrev.00024.2007
Olmedo I, Pino G, Riquelme JA, Aranguiz P, Díaz MC, López-Crisosto C, Lavandero S, Donoso P, Pedrozo Z, Sánchez G (2020) Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury. Biochim Biophys Acta Mol Basis Dis 1866:165659. https://doi.org/10.1016/j.bbadis.2019.165659
Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022. https://doi.org/10.1161/circulationaha.109.906610
Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233. https://doi.org/10.1038/nrm2125
Papanicolaou KN, Kikuchi R, Ngoh GA, Coughlan KA, Dominguez I, Stanley WC, Walsh K (2012) Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res 111:1012–1026. https://doi.org/10.1161/circresaha.112.274142
Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Serena D, Ruggiero FM (1999) Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radic Biol Med 27:42–50. https://doi.org/10.1016/s0891-5849(99)00032-5
Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, Härtel S, Jaimovich E, Zorzano A, Hidalgo C, Lavandero S (2008) Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 77:387–397. https://doi.org/10.1093/cvr/cvm029
Perry CG, Kane DA, Lanza IR, Neufer PD (2013) Methods for assessing mitochondrial function in diabetes. Diabetes 62:1041–1053. https://doi.org/10.2337/db12-1219
Ramachandra CJA, Hernandez-Resendiz S, Crespo-Avilan GE, Lin YH, Hausenloy DJ (2020) Mitochondria in acute myocardial infarction and cardioprotection. EBioMedicine 57:102884. https://doi.org/10.1016/j.ebiom.2020.102884
Raturi A, Simmen T (2013) Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta 1833:213–224. https://doi.org/10.1016/j.bbamcr.2012.04.013
Rossello A, Nuti E, Orlandini E, Carelli P, Rapposelli S, Macchia M, Minutolo F, Carbonaro L, Albini A, Benelli R, Cercignani G, Murphy G, Balsamo A (2004) New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2). Bioorg Med Chem 12:2441–2450. https://doi.org/10.1016/j.bmc.2004.01.047
Rossello X, Hall AR, Bell RM, Yellon DM (2016) Characterization of the Langendorff perfused isolated mouse heart model of global ischemia-reperfusion injury: impact of ischemia and reperfusion length on infarct size and LDH release. J Cardiovasc Pharmacol Ther 21:286–295. https://doi.org/10.1177/1074248415604462
Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832. https://doi.org/10.1016/j.cell.2010.01.040
Shan S, Liu Z, Li L, Zhang C, Kou R, Song F (2022) Calpain-mediated cleavage of mitochondrial fusion/fission proteins in acetaminophen-induced mice liver injury. Hum Exp Toxicol 41:9603271221108320. https://doi.org/10.1177/09603271221108321
Spinelli JB, Haigis MC (2018) The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 20:745–754. https://doi.org/10.1038/s41556-018-0124-1
Thai PN, Seidlmayer LK, Miller C, Ferrero M, Dorn GW II, Schaefer S, Bers DM, Dedkova EN (2019) Mitochondrial quality control in aging and heart failure: influence of ketone bodies and mitofusin-stabilizing peptides. Front Physiol 10:382. https://doi.org/10.3389/fphys.2019.00382
Toldo S, Mezzaroma E, Mauro AG, Salloum F, Van Tassell BW, Abbate A (2015) The inflammasome in myocardial injury and cardiac remodeling. Antioxid Redox Signal 22:1146–1161. https://doi.org/10.1089/ars.2014.5989
Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Ferguson JF, Generoso G, Ho JE, Kalani R, Khan SS, Kissela BM, Knutson KL, Levine DA, Lewis TT, Liu J, Loop MS, Ma J, Mussolino ME, Navaneethan SD, Perak AM, Poudel R, Rezk-Hanna M, Roth GA, Schroeder EB, Shah SH, Thacker EL, VanWagner LB, Virani SS, Voecks JH, Wang NY, Yaffe K, Martin SS (2022) Heart disease and stroke statistics-2022 update: a report from the American heart association. Circulation 145:e153-639. https://doi.org/10.1161/cir.0000000000001052
Uchikado Y, Ikeda Y, Ohishi M (2022) Current understanding of the pivotal role of mitochondrial dynamics in cardiovascular diseases and senescence. Front Cardiovasc Med 9:905072. https://doi.org/10.3389/fcvm.2022.905072
Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, Sagara J, Taniguchi S, Takahashi M (2015) Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm. Arterioscler Thromb Vasc Biol 35:127–136. https://doi.org/10.1161/atvbaha.114.303763
Viappiani S, Nicolescu AC, Holt A, Sawicki G, Crawford BD, León H, van Mulligen T, Schulz R (2009) Activation and modulation of 72kDa matrix metalloproteinase-2 by peroxynitrite and glutathione. Biochem Pharmacol 77:826–834. https://doi.org/10.1016/j.bcp.2008.11.004
Wang J, Zhou H (2020) Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia-reperfusion injury. Acta Pharm Sin B 10:1866–1879. https://doi.org/10.1016/j.apsb.2020.03.004
Wang W, Sawicki G, Schulz R (2002) Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res 53:165–174. https://doi.org/10.1016/s0008-6363(01)00445-x
Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R (2002) Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106:1543–1549. https://doi.org/10.1161/01.cir.0000028818.33488.7b
Wang W, Zhang F, Li L, Tang F, Siedlak SL, Fujioka H, Liu Y, Su B, Pi Y, Wang X (2015) MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons. J Biol Chem 290:168–182. https://doi.org/10.1074/jbc.M114.617167
Wu QR, Zheng DL, Liu PM, Yang H, Li LA, Kuang SJ, Lai YY, Rao F, Xue YM, Lin JJ, Liu SX, Chen CB, Deng CY (2021) High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy. Cell Death Dis 12:216. https://doi.org/10.1038/s41419-021-03502-4
Yamada A, Uegaki A, Nakamura T, Ogawa K (2000) ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs. Inflamm Res 49:144–146. https://doi.org/10.1007/s000110050573
Yang Y, Zhao L, Ma J (2017) Penehyclidine hydrochloride preconditioning provides cardiac protection in a rat model of myocardial ischemia/reperfusion injury via the mechanism of mitochondrial dynamics mechanism. Eur J Pharmacol 813:130–139. https://doi.org/10.1016/j.ejphar.2017.07.031
Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065. https://doi.org/10.1126/science.1219855
Zhang X, Hong S, Qi S, Liu W, Zhang X, Shi Z, Chen W, Zhao M, Yin X (2019) NLRP3 inflammasome is involved in calcium-sensing receptor-induced aortic remodeling in SHRs. Mediators Inflamm 2019:6847087. https://doi.org/10.1155/2019/6847087
Zhao T, Huang X, Han L, Wang X, Cheng H, Zhao Y, Chen Q, Chen J, Cheng H, Xiao R, Zheng M (2012) Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem 287:23615–23625. https://doi.org/10.1074/jbc.M112.379164
Zhou HZ, Ma X, Gray MO, Zhu BQ, Nguyen AP, Baker AJ, Simonis U, Cecchini G, Lovett DH, Karliner JS (2007) Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction. Biochem Biophys Res Commun 358:189–195. https://doi.org/10.1016/j.bbrc.2007.04.094
Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225. https://doi.org/10.1038/nature09663
Funding
Research was supported by Grants from the Canadian Institutes of Health Research (Foundation 143299 to RS and FRN156393 to JMS). WB is supported by an Alberta Innovates Graduate Student Scholarship.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Bassiouni, W., Valencia, R., Mahmud, Z. et al. Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia–reperfusion injury. Basic Res Cardiol 118, 29 (2023). https://doi.org/10.1007/s00395-023-00999-y
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-023-00999-y