Abstract
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite produced along with leukotrienes via the 5-lipoxygenase pathway. Metabolomics studies have shown that 5-oxo-ETE level is elevated in the serum in acute myocardial infarction (AMI). The actions of 5-oxo-ETE are mediated by the highly selective oxoeicosanoid receptor (OXE-R). Moreover, increased OXE-R content was verified in AMI patients and mice. However, the precise role of OXE-R in AMI is unclear. In the present study, we demonstrate that 5-oxo-ETE triggered myocardial injury in mice. Pathway enrichment analysis identified branched chain amino acid transaminase 1/2 (BCAT1/2) as potential mediators of this effect. Western blot and immunohistochemical analyses showed that BCAT1/BCAT2 expression was significantly reduced by AMI in vitro and in vivo, while pharmacologic inhibition of BCAT1/BCAT2 accelerated myocardial injury. Conversely, heart-specific overexpression of BCAT1/BCAT2 in mice protected against ischemic myocardial injury. Treatment with the selective OXE-R inhibitor Gue1654 alleviated coronary artery ligation-induced ischemic myocardial injury in mice and oxygen/glucose deprivation-induced injury in cardiomyocytes through activation of BCAT1, while inhibiting OXE-R suppressed protein kinase C-ε (PKC-ε)/nuclear factor κB (NF-κB) signaling and cardiomyocyte apoptosis. Overall, our study confirmed a novel target OXE-R for the treatment of AMI based on metabolomics, and targeting OXE-R may represent unrecognized therapeutic intervention for cardiovascular diseases through activation of BCAT1.
Similar content being viewed by others
Abbreviations
- 5-oxo-ETE:
-
5-Oxo-6,8,11,14-eicosatetraenoic acid
- OXE-R:
-
Oxoeicosanoid receptor
- AMI:
-
Acute myocardial infarction
- BCAA:
-
Branched chain amino acid
- BCAT1:
-
Branched-chain-amino-acid aminotransferase, cytosolic
- BCAT2:
-
Branched-chain-amino-acid aminotransferase, mitochondrial
- CAL:
-
Left anterior descending coronary artery ligation
- CK:
-
Creatine kinase
- CRP:
-
C-reactive protein
- cTn-I:
-
Cardiac troponin I
- HPLC-Q/TOF–MS:
-
High-performance liquid chromatography and quadrupole time-of-flight mass spectrometry
- LDH:
-
Lactate dehydrogenase
- mTOR:
-
Mammalian target of rapamycin
- NF-κB:
-
Nuclear factor kappa-B
- OPLS-DA:
-
Orthogonal partial least-squares discriminant analysis
- PKC-ε :
-
Protein kinase c-ε
- p-mTOR:
-
Phosphorylated-mammalian target of rapamycin
- PCA:
-
Principal component analysis
- TNF-α:
-
Tumor necrosis factor-α
- VIP:
-
Variables importance in the projection
- FLC:
-
Ferritin light chain
- FHC:
-
Ferritin heavy chain
- GPX4:
-
Glutathione peroxidase 4
- KLF15:
-
Krüppel-like factor 15
- BCKDHA:
-
Branched-chain keto acid dehydrogenase E1 component α chain
- BCKDHB:
-
Branched chain keto acid dehydrogenase E1, β polypeptide
- PFK1:
-
Phosphofructokinase
References
Blättermann S, Peters L, Ottersbach PA, Bock A, Konya V, Weaver CD, Gonzalez A, Schröder R, Tyagi R, Luschnig P, Gäb J, Hennen S, Ulven T, Pardo L, Mohr K, Gütschow M, Heinemann A, Kostenis E (2012) A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer. Nat Chem Biol 8:631–638. https://doi.org/10.1038/nchembio.962
Bøtker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femminò S, García-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhäuser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schlüter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8
Castillo EC, Morales JA, Chapoy-Villanueva H, Silva-Platas C, Treviño-Saldaña N, Guerrero-Beltrán CE, Bernal-Ramírez J, Torres-Quintanilla A, García N, Youker K, Torre-Amione G, García-Rivas G (2019) Mitochondrial hyperacetylation in the failing hearts of obese patients mediated partly by a reduction in SIRT3: the involvement of the mitochondrial permeability transition pore. Cell Physiol Biochem 53:465–479. https://doi.org/10.33594/000000151
Chang L, Wang Z, Ma F, Tran B, Zhong R, Xiong Y, Dai T, Wu J, Xin X, Guo W, Xie Y, Mao Y, Zhu Y-Z (2019) ZYZ-803 mitigates endoplasmic reticulum stress-related necroptosis after acute myocardial infarction through downregulating the RIP3-CaMKII signaling pathway. Oxid Med Cell Longev 2019:6173685. https://doi.org/10.1155/2019/6173685
Cormier SA, Taranova AG, Bedient C, Nguyen T, Protheroe C, Pero R, Dimina D, Ochkur SI, O’Neill K, Colbert D, Lombari TR, Constant S, McGarry MP, Lee JJ, Lee NA (2006) Pivotal Advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J Leukoc Biol 79:1131–1139. https://doi.org/10.1189/jlb.0106027
Csonka C, Kupai K, Bencsik P, Görbe A, Pálóczi J, Zvara A, Puskás LG, Csont T, Ferdinandy P (2014) Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide. Am J Physiol Heart Circ Physiol 306:H405–H413. https://doi.org/10.1152/ajpheart.00257.2013
Czibik G, Steeples V, Yavari A, Ashrafian H (2014) Citric acid cycle intermediates in cardioprotection. Circ Cardiovasc Genet 7:711–719. https://doi.org/10.1161/CIRCGENETICS.114.000220
Fan Y, Li Y, Chen Y, Zhao Y-J, Liu L-W, Li J, Wang S-L, Alolga RN, Yin Y, Wang X-M, Zhao D-S, Shen J-H, Meng F-Q, Zhou X, Xu H, He G-P, Lai M-D, Li P, Zhu W, Qi L-W (2016) Comprehensive metabolomic characterization of coronary artery diseases. J Am Coll Cardiol 68:1281–1293. https://doi.org/10.1016/j.jacc.2016.06.044
Fattore E, Fanelli R (2013) Palm oil and palmitic acid: a review on cardiovascular effects and carcinogenicity. Int J Food Sci Nutr 64:648–659. https://doi.org/10.3109/09637486.2013.768213
Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174. https://doi.org/10.1124/pr.113.008300
Ganna A, Salihovic S, Sundström J, Broeckling CD, Hedman AK, Magnusson PKE, Pedersen NL, Larsson A, Siegbahn A, Zilmer M, Prenni J, Arnlöv J, Lind L, Fall T, Ingelsson E (2014) Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease. PloS Genet 10:e1004801. https://doi.org/10.1371/journal.pgen.1004801
Giricz Z, Görbe A, Pipis J, Burley DS, Ferdinandy P, Baxter GF (2009) Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3’,5’-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats. Br J Pharmacol 158:1495–1502. https://doi.org/10.1111/j.1476-5381.2009.00424.x
Hanna VS, Hafez EAA (2018) Synopsis of arachidonic acid metabolism: a review. J Adv Res 11:23–32. https://doi.org/10.1016/j.jare.2018.03.005
Heusch G (2020) Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 17:773–789. https://doi.org/10.1038/s41569-020-0403-y
Heusch G, Kleinbongard P (2020) Is metoprolol more cardioprotective than other beta-blockers? Eur Heart J 41:4441–4443. https://doi.org/10.1093/eurheartj/ehaa764
Hosoi T, Koguchi Y, Sugikawa E, Chikada A, Ogawa K, Tsuda N, Suto N, Tsunoda S, Taniguchi T, Ohnuki T (2002) Identification of a novel human eicosanoid receptor coupled to G(i/o). J Biol Chem 277:31459–31465. https://doi.org/10.4049/jimmunol.1302013
Huang S, Cao Y (2020) Correlation of cathepsin S with coronary stenosis degree, carotid thickness, blood pressure, glucose and lipid metabolism and vascular endothelial function in atherosclerosis. Exp Ther Med 19:61–66. https://doi.org/10.3892/etm.2019.8222
Hutson SM (2006) The case for regulating indispensable amino acid metabolism: the branched-chain alpha-keto acid dehydrogenase kinase-knockout mouse. Biochem J 400:e1–e3. https://doi.org/10.1046/j.1471-4159.2001.00156.x
Hutson SM, Sweatt AJ, Lanoue KF (2005) Branched-chain amino acid metabolism: implications for establishing safe intakes. J Nutr 135:1557S-1564S. https://doi.org/10.1093/jn/135.6.1557s
Ichihara A, Koyama E (1966) Transaminase of branched chain amino acids. I. Branched chain amino acids-alpha-ketoglutarate transaminase. J Biochem 59:160–169. https://doi.org/10.1093/oxfordjournals.jbchem.a128277
Jones CE, Holden S, Tenaillon L, Bhatia U, Seuwen K, Tranter P, Turner J, Kettle R, Bouhelal R, Charlton S, Nirmala NR, Jarai G, Finan P (2003) Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils. Mol Pharmacol 63:471–477. https://doi.org/10.1124/mol.63.3.471
Kim-Campbell N, Gretchen C, Ritov VB, Kochanek PM, Balasubramani GK, Kenny E, Sharma M, Viegas M, Callaway C, Kagan VE, Bayír H (2020) Bioactive oxylipins in infants and children with congenital heart disease undergoing pediatric cardiopulmonary bypass. Pediatr Crit Care Med 21:33–41. https://doi.org/10.1097/PCC.0000000000002036
Kleinbongard P (2020) Cardioprotection by early metoprolol—attenuation of ischemic vs. reperfusion injury? Basic Res Cardiol 115:54. https://doi.org/10.1007/s00395-020-0814-2
Konya V, Blättermann S, Jandl K, Platzer W, Ottersbach PA, Marsche G, Gütschow M, Kostenis E, Heinemann A (2014) A biased non-Gαi OXE-R antagonist demonstrates that Gαi protein subunit is not directly involved in neutrophil, eosinophil, and monocyte activation by 5-oxo-ETE. J Immunol 192:4774–4782. https://doi.org/10.4049/jimmunol.1302013
Kuhn TC, Knobel J, Burkert-Rettenmaier S, Li X, Meyer IS, Jungmann A, Sicklinger F, Backs J, Lasitschka F, Müller OJ, Katus HA, Krijgsveld J, Leuschner F (2020) Secretome analysis of cardiomyocytes identifies PCSK6 as a novel player in cardiac remodeling after myocardial infarction. Circulation 141:1628–1644. https://doi.org/10.1161/CIRCULATIONAHA.119.044914
Li F, Fan X, Zhang Y, Pang L, Ma X, Song M, Kou J, Yu B (2016) Cardioprotection by combination of three compounds from ShengMai preparations in mice with myocardial ischemia/reperfusion injury through AMPK activation-mediated mitochondrial fission. Sci Rep 6:37114. https://doi.org/10.1038/srep37114
Li R, Zhang J, Gao Y, Li J, Yan B, Wang G (2019) Impact of lung function and SDB on incident myocardial infarction and heart failure: a community-based study. Lung 197:339–347. https://doi.org/10.1007/s00408-019-00229-0
Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76:1712–1723. https://doi.org/10.1074/jbc.M203194200
Lindon JC, Nicholson JK, Holmes E (2011) The handbook of metabonomics and metabolomics. Elsevier, Amsterdam
Lobo-Gonzalez M, Galán-Arriola C, Rossello X, González-Del-Hoyo M, Vilchez JP, Higuero-Verdejo MI, García-Ruiz JM, López-Martín GJ, Sánchez-González J, Oliver E, Pizarro G, Fuster V, Ibanez B (2020) Metoprolol blunts the time-dependent progression of infarct size. Basic Res Cardiol 115:55. https://doi.org/10.1007/s00395-020-0812-4
Lorca R, Jiménez-Blanco M, García-Ruiz JM, Pizarro G, Fernández-Jiménez R, García-Álvarez A, Fernández-Friera L, Lobo-González M, Fuster V, Rossello X, Ibáñez B (2020) Coexistence of transmural and lateral wavefront progression of myocardial infarction in the human heart. Rev Esp Cardiol S1885–5857(20):30336–30344. https://doi.org/10.1016/j.rec.2020.07.007
Magaye RR, Savira F, Hua Y, Xiong X, Huang L, Reid C, Flynn B, Kaye D, Liew D, Wang BH (2020) Exogenous dihydrosphingosine 1 phosphate mediates collagen synthesis in cardiac fibroblasts through JAK/STAT signalling and regulation of TIMP1. Cell Signal 72:109629. https://doi.org/10.1016/j.cellsig.2020.109629
Misra A, Haudek SB, Knuefermann P, Vallejo JG, Chen ZJ, Michael LH, Sivasubramanian N, Olson EN, Entman ML, Mann DL (2003) Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction. Circulation 108:3075–3078. https://doi.org/10.1161/01.CIR.0000108929.93074.0B
Morris J, Dunham A (2020) Metoprolol. In: StatPearls. Treasure Island, Florida
Newby LK (2019) Inflammation as a treatment target after acute myocardial infarction. N Engl J Med 381:2562–2563. https://doi.org/10.1056/NEJMe1914378
Peron G, Sut S, Dal Ben S, Voinovich D, Dall’Acqua S (2020) Untargeted UPLC-MS metabolomics reveals multiple changes of urine composition in healthy adult volunteers after consumption of Curcuma longa L. extract. Food Res Int 127:108730. https://doi.org/10.1016/j.foodres.2019.108730
Powell WS, Rokach J (2015) Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid. Biochim Biophys Acta 1851:340–355. https://doi.org/10.1016/j.bbalip.2014.10.008
Powell WS, Rokach J (2013) The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor. Prog Lipid Res 52:651–665. https://doi.org/10.1016/j.plipres.2013.09.001
Powell WS, Chung D, Gravel S (1995) 5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration. J Immunol 154:4123–4132
Qi JY, Tan YF, Fan DC, Pan WJ, Yu J, Xu W, Wu JS, Zhang MZ (2020) Songling Xuemaikang Capsule inhibits isoproterenol-induced cardiac hypertrophy via CaMKII δ and ERK1/2 pathways. J Ethnopharmacol 253:112660. https://doi.org/10.1016/j.jep.2020.112660
Qi W, Keenan HA, Li Q, Ishikado A, Kannt A, Sadowski T, Yorek MA, Wu IH, Lockhart S, Coppey LJ, Pfenninger A, Liew CW, Qiang G, Burkart AM, Hastings S, Pober D, Cahill C, Niewczas MA, Israelsen WJ, Tinsley L, Stillman IE, Amenta PS, Feener EP, Vander Heiden MG, Stanton RC, King GL (2017) Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 23:753–762. https://doi.org/10.1038/nm.4328
Reed GW, Rossi JE, Cannon CP (2017) Acute myocardial infarction. Lancet 389:197–210. https://doi.org/10.1016/S0140-6736(16)30677-8
Roffi M, Patrono C, Collet J-P, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S (2016) 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 37:267–315. https://doi.org/10.1093/eurheartj/ehv320
Sabatine MS, Liu E, Morrow DA, Heller E, McCarroll R, Wiegand R, Berriz GF, Roth FP, Gerszten RE (2005) Metabolomic identification of novel biomarkers of myocardial ischemia. Circulation 112:3868–3875. https://doi.org/10.1161/CIRCULATIONAHA.105.569137
Salabei JK, Lorkiewicz PK, Holden CR, Li Q, Hong KU, Bolli R, Bhatnagar A, Hill BG (2015) Glutamine regulates cardiac progenitor cell metabolism and proliferation. Stem Cells 33:2613–2627. https://doi.org/10.1002/stem.2047
Shah SH, Kraus WE, Newgard CB (2012) Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. Circulation 126:1110–1120. https://doi.org/10.1161/CIRCULATIONAHA.111.060368
Sibilitz KL, Benn M, Nordestgaard BG (2014) Creatinine, eGFR and association with myocardial infarction, ischemic heart disease and early death in the general population. Atherosclerosis 237:67–75. https://doi.org/10.1016/j.atherosclerosis.2014.08.040
Souza WM, Heck TG, Wronski EC, Ulbrich AZ, Boff E (2013) Effects of creatine supplementation on biomarkers of hepatic and renal function in young trained rats. Toxicol Mech Method 23:697–701. https://doi.org/10.3109/15376516.2013.843108
Spath NB, Mills NL, Cruden NL (2016) Novel cardioprotective and regenerative therapies in acute myocardial infarction: a review of recent and ongoing clinical trials. Future Cardiol 12:655–672. https://doi.org/10.2217/fca-2016-0044
Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van’t Hof A, Widimsky P, Zahger D (2012) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33:2569–2619. https://doi.org/10.1093/eurheartj/ehs215
Sturm GJ, Schuligoi R, Sturm EM, Royer JF, Lang-Loidolt D, Stammberger H, Amann R, Peskar BA, Heinemann A (2005) 5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent chemoattractant for human basophils. J Allergy Clin Immunol 116:1014–1019. https://doi.org/10.1016/j.jaci.2005.08.001
Tang WH, Wang Z, Cho L, Brennan DM, Hazen SL (2009) Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J Am Coll Cardiol 53:2061–2067. https://doi.org/10.1016/j.jacc.2009.02.036
Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AHC, Karra D, Piro RM, Felsberg J, Addington A, Lemke D, Weibrecht I, Hovestadt V, Rolli CG, Campos B, Turcan S, Sturm D, Witt H, Chan TA, Herold-Mende C, Kemkemer R, König R, Schmidt K, Hull W-E, Pfister SM, Jugold M, Hutson SM, Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B (2013) BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19:901–908. https://doi.org/10.1038/nm.3217
Wegmann M (2011) Targeting eosinophil biology in asthma therapy. Am J Respir Cell Mol Biol 45:667–674. https://doi.org/10.1165/rcmb.2011-0013TR
Zhang H, Yang YH, Yan B, Tang X, Cheng XR, Le GW, Shi YH (2018) Dityrosine administration induces myocardium injury and inflammatory response in mice. Wei Sheng Yan Jiu 47:345–351
Zhang L, Wei TT, Li Y, Li J, Fan Y, Huang FQ, Cai YY, Ma G, Liu JF, Chen QQ, Wang SL, Li H, Alolga RN, Liu B, Zhao DS, Shen JH, Wang XM, Zhu W, Li P, Qi LW (2018) Functional metabolomics characterizes a key role for N-acetylneuraminic acid in coronary artery diseases. Circulation 137:1374–1390. https://doi.org/10.1161/CIRCULATIONAHA.117.031139
Acknowledgements
We thank Xiaonan Ma (School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University) for help with laser confocal microscopy.
Funding
This research work was supported by the National Natural Science Foundation of China (No. 81774150, No. 81973506, No. 81603328, No. 81573719), Natural Science Foundation of Jiangsu Province (BK20160761), Project funded by China Postdoctoral Science Foundation (2016M600456, 2017T100425), and supported by "Double First-Class" University project (CPU2018GF06, CPU2018GF07), and the Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (NO. ZYX03KF031).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declared that they have no conflict of interest.
Ethics approval
All animal experiments were performed in accordance to guidelines of the local animal ethics committee.
Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lai, Q., Yuan, G., Shen, L. et al. Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1. Basic Res Cardiol 116, 3 (2021). https://doi.org/10.1007/s00395-021-00844-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-021-00844-0