Top

Published in:

Open Access 01-03-2019 | Myocardial Infarction | Original Contribution

Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia–reperfusion injury

Authors: Tarja Alakoski, Johanna Ulvila, Raisa Yrjölä, Laura Vainio, Johanna Magga, Zoltan Szabo, Jonathan D. Licht, Risto Kerkelä

Published in: Basic Research in Cardiology | Issue 2/2019

Abstract

Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia–reperfusion (I/R) injury. Infarct areas of mouse hearts showed an increase in Spry1 protein expression, which localized to cardiomyocytes. To investigate if cardiomyocyte Spry1 regulates I/R injury, 8-week-old inducible cardiomyocyte Spry1 knockout (Spry1 cKO) mice and control mice were subjected to cardiac I/R injury. Spry1 cKO mice showed reduction in release of cardiac troponin I and reduced infarct size after I/R injury compared to control mice. Similar to Spry1 knockdown in cardiomyocytes in vivo, RNAi-mediated Spry1 silencing in isolated cardiomyocytes improved cardiomyocyte survival following simulated ischemia injury. Mechanistically, Spry1 knockdown induced cardiomyocyte extracellular signal-regulated kinase (ERK) phosphorylation in healthy hearts and isolated cardiomyocytes, and enhanced ERK phosphorylation after I/R injury. Spry1-deficient cardiomyocytes showed better preserved mitochondrial membrane potential following ischemic injury and an increase in levels of phosphorylated ERK and phosphorylated glycogen synthase kinase-3β (GSK-3β) in mitochondria of hypoxic cardiomyocytes. Overexpression of constitutively active GSK-3β abrogated the protective effect of Spry1 knockdown. Moreover, pharmacological inhibition of GSK-3β protected wild-type cardiomyocytes from cell death, but did not further protect Spry1-silenced cardiomyocytes from hypoxia-induced injury. Cardiomyocyte Spry1 knockdown promotes ERK phosphorylation and offers protection from I/R injury. Our findings indicate that Spry1 is an important regulator of cardiomyocyte viability during ischemia–reperfusion injury.

Available only for authorised users

Anderson K, Nordquist KA, Gao X, Hicks KC, Zhai B, Gygi SP, Patel TB (2011) Regulation of cellular levels of Sprouty2 protein by prolyl hydroxylase domain and von Hippel–Lindau proteins. J Biol Chem 286:42027–42036. https://doi.org/10.1074/jbc.M111.303222 CrossRefPubMedPubMedCentral

Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197. https://doi.org/10.1161/01.CIR.0000151290.04952.3B CrossRefPubMed

Basson MA, Akbulut S, Watson-Johnson J, Simon R, Carroll TJ, Shakya R, Gross I, Martin GR, Lufkin T, McMahon AP, Wilson PD, Costantini FD, Mason IJ, Licht JD (2005) Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell 8:229–239. https://doi.org/10.1016/j.devcel.2004.12.004 CrossRefPubMed

Beurel E, Grieco SF, Jope RS (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114–131. https://doi.org/10.1016/j.pharmthera.2014.11.016 CrossRefPubMed

Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter 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 CrossRefPubMedPubMedCentral

Charles NJ, Huebert RC, Lee S, Adhikari N, Polster S, Rider JE, Braunlin E, Mariash A, Robledo M, Schuweiler D, Hall JL (2010) Targeted Sprouty1 overexpression in cardiac myocytes does not alter myocardial remodeling or function. Mol Cell Biochem 342:57–62. https://doi.org/10.1007/s11010-010-0468-8 CrossRefPubMedPubMedCentral

Das A, Salloum FN, Xi L, Rao YJ, Kukreja RC (2009) ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. Am J Physiol Heart Circ Physiol 296:H1236–H1243. https://doi.org/10.1152/ajpheart.00100.2009 CrossRefPubMedPubMedCentral

Davidson SM, Arjun S, Basalay MV, Bell RM, Bromage DI, Botker HE, Carr RD, Cunningham J, Ghosh AK, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Maddock H, Ovize M, Walker M, Wiart M, Yellon DM (2018) The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. Basic Res Cardiol 113:43. https://doi.org/10.1007/s00395-018-0704-z CrossRefPubMedPubMedCentral

Denise Martin E, De Nicola GF, Marber MS (2012) New therapeutic targets in cardiology: p38 alpha mitogen-activated protein kinase for ischemic heart disease. Circulation 126:357–368. https://doi.org/10.1161/CIRCULATIONAHA.111.071886 CrossRefPubMed

10.

Ding Q, Xia W, Liu J-C, Yang J-Y, Lee D-F, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai C-C, Tsai F-J, Tsai C-H, Hung M-C (2005) Erk associates with and primes GSK-3β for Its inactivation resulting in upregulation of β-catenin. Mol Cell 19:159–170. https://doi.org/10.1016/j.molcel.2005.06.009 CrossRefPubMed

11.

Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG (2004) Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 27:107–144. https://doi.org/10.1146/annurev.neuro.27.070203.144206 CrossRefPubMed

12.

Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, Fan Q, Chuprun JK, Ma XL, Koch WJ (2010) A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res 107:1445–1453. https://doi.org/10.1161/CIRCRESAHA.110.223925 CrossRefPubMedPubMedCentral

13.

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2014) Heart disease and stroke statistics-2014 update: a report from the American Heart Association. Circulation 129:e28–e292. https://doi.org/10.1161/01.cir.0000441139.02102.80 CrossRefPubMed

14.

Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M (2008) Inhibition of GSK3β by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 117:2761–2768. https://doi.org/10.1161/circulationaha.107.755066 CrossRefPubMed

15.

Hanafusa H, Torii S, Yasunaga T, Nishida E (2002) Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4:850–858. https://doi.org/10.1038/ncb867 CrossRefPubMed

16.

Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D (2016) Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 111:70. https://doi.org/10.1007/s00395-016-0588-8 CrossRefPubMedPubMedCentral

17.

Hausenloy DJ, Yellon DM (2013) Myocardial ischemia–reperfusion injury: a neglected therapeutic target. J Clin Invest 123:92–100. https://doi.org/10.1172/JCI62874 CrossRefPubMedPubMedCentral

18.

Hausenloy DJ, Yellon DM (2006) Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70:240–253. https://doi.org/10.1016/j.cardiores.2006.01.017 CrossRefPubMed

19.

Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658. https://doi.org/10.1161/CIRCRESAHA.116.308640 CrossRefPubMed

20.

Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. https://doi.org/10.1161/circresaha.116.305348 CrossRefPubMed

21.

Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 110:111–115. https://doi.org/10.1161/CIRCRESAHA.111.259556 CrossRefPubMed

22.

Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF (1975) Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 56:978–985. https://doi.org/10.1172/JCI108178 CrossRefPubMedPubMedCentral

23.

Huebert RC, Li Q, Adhikari N, Charles NJ, Han X, Ezzat MK, Grindle S, Park S, Ormaza S, Fermin D, Miller LW, Hall JL (2004) Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. Physiol Genom 18:284–289. https://doi.org/10.1152/physiolgenomics.00098.2004 CrossRef

24.

Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549. https://doi.org/10.1172/JCI19906 CrossRefPubMedPubMedCentral

25.

Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, Sollott SJ (2009) Role of glycogen synthase kinase-3beta in cardioprotection. Circ Res 104:1240–1252. https://doi.org/10.1161/CIRCRESAHA.109.197996 CrossRefPubMedPubMedCentral

26.

Kwong Jennifer Q, Molkentin Jeffery D (2015) Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab 21:206–214. https://doi.org/10.1016/j.cmet.2014.12.001 CrossRefPubMedPubMedCentral

27.

Lavoie H, Therrien M (2015) Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 16:281–298. https://doi.org/10.1038/nrm3979 CrossRefPubMed

28.

Lemmon MA, Schlessinger J (2010) Cell signaling by receptor-tyrosine kinases. Cell 141:1117–1134. https://doi.org/10.1016/j.cell.2010.06.011 CrossRefPubMedPubMedCentral

29.

Lips DJ, Bueno OF, Wilkins BJ, Purcell NH, Kaiser RA, Lorenz JN, Voisin L, Saba-El-Leil MK, Meloche S, Pouyssegur J, Pages G, De Windt LJ, Doevendans PA, Molkentin JD (2004) MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 109:1938–1941. https://doi.org/10.1161/01.CIR.0000127126.73759.23 CrossRefPubMed

30.

Ma XL, Kumar S, Gao F, Louden CS, Lopez BL, Christopher TA, Wang C, Lee JC, Feuerstein GZ, Yue TL (1999) Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99:1685–1691. https://doi.org/10.1161/circ.99.13.1685 CrossRefPubMed

31.

Mason JM, Morrison DJ, Albert Basson M, Licht JD (2006) Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 16:45–54. https://doi.org/10.1016/j.tcb.2005.11.004 CrossRefPubMed

32.

Mason JM, Morrison DJ, Bassit B, Dimri M, Band H, Licht JD, Gross I (2004) Tyrosine phosphorylation of sprouty proteins regulates their ability to inhibit growth factor signaling: a dual feedback loop. Mol Biol Cell 15:2176–2188. https://doi.org/10.1091/mbc.E03-07-0503 CrossRefPubMedPubMedCentral

33.

Masoumi-Moghaddam S, Amini A, Morris DL (2014) The developing story of Sprouty and cancer. Cancer Metastasis Rev 33:695–720. https://doi.org/10.1007/s10555-014-9497-1 CrossRefPubMedPubMedCentral

34.

Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–760. https://doi.org/10.1016/j.molcel.2006.02.009 CrossRefPubMed

35.

Minowada G, Jarvis LA, Chi CL, Neubuser A, Sun X, Hacohen N, Krasnow MA, Martin GR (1999) Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 126:4465–4475PubMed

36.

Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM (2000) The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. Basic Res Cardiol 95:472–478. https://doi.org/10.1007/s003950070023 CrossRefPubMed

37.

Nakano A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, Critz SD (2000) Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circ Res 86:144–151. https://doi.org/10.1161/res.86.2.144 CrossRefPubMed

38.

Nakano A, Cohen MV, Critz S, Downey JM (2000) SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts. Basic Res Cardiol 95:466–471. https://doi.org/10.1007/s003950070022 CrossRefPubMed

39.

Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, Cai G, de Winter RJ, Hamm CW, Heitner JF, Kim R, Lerman A, Patel MR, Tanguay JF, Lepore JJ, Al-Khalidi HR, Sprecher DL, Granger CB, Investigators S (2014) Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet 384:1187–1195. https://doi.org/10.1016/S0140-6736(14)60417-7 CrossRefPubMed

40.

Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno M (2001) ERK pathway positively regulates the expression of Sprouty genes. Biochem Biophys Res Commun 285:1084–1088. https://doi.org/10.1006/bbrc.2001.5295 CrossRefPubMed

41.

Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD (2007) Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA 104:14074–14079. https://doi.org/10.1073/pnas.0610906104 CrossRefPubMedPubMedCentral

42.

Rose BA, Force T, Wang Y (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507–1546. https://doi.org/10.1152/physrev.00054.2009 CrossRefPubMed

43.

Rossello X, Yellon DM (2017) The RISK pathway and beyond. Basic Res Cardiol 113:2. https://doi.org/10.1007/s00395-017-0662-x CrossRefPubMedPubMedCentral

44.

Sanada S, Kitakaze M, Papst PJ, Hatanaka K, Asanuma H, Aki T, Shinozaki Y, Ogita H, Node K, Takashima S, Asakura M, Yamada J, Fukushima T, Ogai A, Kuzuya T, Mori H, Terada N, Yoshida K, Hori M (2001) Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart. Circ Res 88:175–180. https://doi.org/10.1161/res.88.2.175 CrossRefPubMed

45.

Schulz R, Belosjorow S, Gres P, Jansen J, Michel MC, Heusch G (2002) p38 MAP kinase is a mediator of ischemic preconditioning in pigs. Cardiovasc Res 55:690–700. https://doi.org/10.1016/S0008-6363(02)00319-X CrossRefPubMed

46.

Sharma B, Joshi S, Sassano A, Majchrzak B, Kaur S, Aggarwal P, Nabet B, Bulic M, Stein BL, McMahon B, Baker DP, Fukunaga R, Altman JK, Licht JD, Fish EN, Platanias LC (2012) Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses. J Biol Chem 287:42352–42360. https://doi.org/10.1074/jbc.M112.400721 CrossRefPubMedPubMedCentral

47.

Sugden PH, Clerk A (1997) Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 9:337–351. https://doi.org/10.1016/S0898-6568(96)00191-X CrossRefPubMed

48.

Sutherland C, Leighton IA, Cohen P (1993) Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 296:15–19. https://doi.org/10.1042/bj2960015 CrossRefPubMedPubMedCentral

49.

Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320:667–670. https://doi.org/10.1126/science.1156037 CrossRefPubMedPubMedCentral

50.

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456:980–984. https://doi.org/10.1038/nature07511 CrossRefPubMed

51.

Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC, Feuerstein GZ, Thomas H, Maleeff B, Ohlstein EH (2000) Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 86:692–699. https://doi.org/10.1161/res.86.6.692 CrossRefPubMed

52.

Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J (2011) Differential roles of GSK-3beta during myocardial ischemia and ischemia/reperfusion. Circ Res 109:502–511. https://doi.org/10.1161/CIRCRESAHA.111.249532 CrossRefPubMedPubMedCentral

Title: Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia–reperfusion injury
Authors: Tarja Alakoski
Johanna Ulvila
Raisa Yrjölä
Laura Vainio
Johanna Magga
Zoltan Szabo
Jonathan D. Licht
Risto Kerkelä
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Keyword: Myocardial Infarction
Published in: Basic Research in Cardiology / Issue 2/2019
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-018-0713-y

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

At a glance: The STEP trials

Springer Medicine

Inhibition of cardiomyocyte Sprouty1 protects from cardiac ischemia–reperfusion injury

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2019

Effect of pulmonary artery denervation in postcapillary pulmonary hypertension: results of a randomized controlled translational study

Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling

Pericardial fluid: an underrated molecular library of heart conditions and a potential vehicle for cardiac therapy

Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction

Blocking the IL-1β signalling pathway prevents chronic viral myocarditis and cardiac remodeling

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page