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Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore

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Abstract

Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size. Western blot analysis on areas at risk from the different mouse groups showed that AZP-531 activates Akt, ERK1-2 as well as S6 and 4EBP1, mTORC1 effectors. We also showed an inhibition of caspase 3 cleavage and Bax translocation to the mitochondria. AZP-531 also stimulated the expression of antioxidants and was capable of decreasing mitochondrial H2O2 production, contributing to the reduction of ROS accumulation. AZP-531 exhibits cardioprotective effect when administrated for postconditioning in C57BL6 mouse IR model. Treatment with AZP-531 rescued the myocardium from cell death at early reperfusion by stimulating protein synthesis, inhibiting Bax/caspase 3-induced apoptosis as well as ROS accumulation and oxidative stress-induced necrosis. AZP-531 may prove useful in the treatment of IR injury.

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References

  1. Abrial M, Da Silva CC, Pillot B, Augeul L, Ivanes F, Teixeira G, Cartier R, Angoulvant D, Ovize M, Ferrera R (2014) Cardiac fibroblasts protect cardiomyocytes against lethal ischemia-reperfusion injury. J Mol Cell Cardiol 68:56–65. doi:10.1016/j.yjmcc.2014.01.005

    Article  CAS  PubMed  Google Scholar 

  2. Allas SDT, Ngo B, Julien M, Sahakian P, Ritter P, van der Lely AJ, Abribat T (2015) Short-term safety, pharmacocinetic (PK) and pharmacodynamic (PD) of AZP-531, an Unacylated Ghremlin (UAG) analog in healthy and overweight/obese subjects. In: 75th Scientific Sessions of American Association, Boston

  3. Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J, Robert D, Ovize M (2005) Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 38:367–374. doi:10.1016/j.yjmcc.2004.12.001

    Article  CAS  PubMed  Google Scholar 

  4. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159:1029–1037. doi:10.1083/jcb.200207165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Benso A, St-Pierre DH, Prodam F, Gramaglia E, Granata R, van der Lely AJ, Ghigo E, Broglio F (2012) Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans. Eur J Endocrinol 166:911–916. doi:10.1530/EJE-11-0982

    Article  CAS  PubMed  Google Scholar 

  6. Bolli R (1991) Oxygen-derived free radicals and myocardial reperfusion injury: an overview. Cardiovasc Drugs Ther 5(Suppl 2):249–268

    Article  PubMed  Google Scholar 

  7. Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E (2004) Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 89:3062–3065. doi:10.1210/jc.2003-031964

    Article  CAS  PubMed  Google Scholar 

  8. Chung H, Seo S, Moon M, Park S (2008) Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol 198:511–521. doi:10.1677/JOE-08-0160

    Article  CAS  PubMed  Google Scholar 

  9. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guerin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Rande JL, Unterseeh T, Le Breton H, Beard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (2015) Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 373:1021–1031. doi:10.1056/NEJMoa1505489

    Article  CAS  PubMed  Google Scholar 

  10. Das A, Salloum FN, Durrant D, Ockaili R, Kukreja RC (2012) Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway. J Mol Cell Cardiol 53:858–869. doi:10.1016/j.yjmcc.2012.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Delhanty PJ, Huisman M, Baldeon-Rojas LY, van den Berge I, Grefhorst A, Abribat T, Leenen PJ, Themmen AP, van der Lely AJ (2013) Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. FASEB J 27:1690–1700. doi:10.1096/fj.12-221143

    Article  CAS  PubMed  Google Scholar 

  12. Delhanty PJ, Neggers SJ, van der Lely AJ (2013) Des-acyl ghrelin: a metabolically active peptide. Endocr Dev 25:112–121. doi:10.1159/000346059

    CAS  PubMed  Google Scholar 

  13. Favaro E, Granata R, Miceli I, Baragli A, Settanni F, Cavallo Perin P, Ghigo E, Camussi G, Zanone MM (2012) The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways. Diabetologia 55:1058–1070. doi:10.1007/s00125-011-2423-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM (2004) Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 279:21085–21095. doi:10.1074/jbc.M400063200

    Article  CAS  PubMed  Google Scholar 

  15. Gharib A, De Paulis D, Li B, Augeul L, Couture-Lepetit E, Gomez L, Angoulvant D, Ovize M (2012) Opposite and tissue-specific effects of coenzyme Q2 on mPTP opening and ROS production between heart and liver mitochondria: role of complex I. J Mol Cell Cardiol 52:1091–1095. doi:10.1016/j.yjmcc.2012.02.005

    Article  CAS  PubMed  Google Scholar 

  16. Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F, Ghe C, Isgaard J, Papotti M, Ghigo E, Muccioli G (2007) Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 148:512–529. doi:10.1210/en.2006-0266

    Article  CAS  PubMed  Google Scholar 

  17. Granata R, Settanni F, Julien M, Nano R, Togliatto G, Trombetta A, Gallo D, Piemonti L, Brizzi MF, Abribat T, van Der Lely AJ, Ghigo E (2012) Des-acyl ghrelin fragments and analogues promote survival of pancreatic beta-cells and human pancreatic islets and prevent diabetes in streptozotocin-treated rats. J Med Chem 55:2585–2596. doi:10.1021/jm201223m

    Article  CAS  PubMed  Google Scholar 

  18. Haupt S, Berger M, Goldberg Z, Haupt Y (2003) Apoptosis—the p53 network. J Cell Sci 116:4077–4085. doi:10.1242/jcs.00739

    Article  CAS  PubMed  Google Scholar 

  19. Hausenloy DJ, Yellon DM (2004) New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 61:448–460. doi:10.1016/j.cardiores.2003.09.024

    Article  CAS  PubMed  Google Scholar 

  20. Hung CM, Garcia-Haro L, Sparks CA, Guertin DA (2012) mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a008771

    Google Scholar 

  21. Hwang S, Moon M, Kim S, Hwang L, Ahn KJ, Park S (2009) Neuroprotective effect of ghrelin is associated with decreased expression of prostate apoptosis response-4. Endocr J 56:609–617

    Article  CAS  PubMed  Google Scholar 

  22. Ibanez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471. doi:10.1016/j.jacc.2015.02.032

    Article  PubMed  Google Scholar 

  23. Inhoff T, Monnikes H, Noetzel S, Stengel A, Goebel M, Dinh QT, Riedl A, Bannert N, Wisser AS, Wiedenmann B, Klapp BF, Tache Y, Kobelt P (2008) Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats. Peptides 29:2159–2168. doi:10.1016/j.peptides.2008.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Inserte J, Barba I, Hernando V, Garcia-Dorado D (2009) Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium. Cardiovasc Res 81:116–122. doi:10.1093/cvr/cvn260

    Article  CAS  PubMed  Google Scholar 

  25. Inserte J, Cardona M, Poncelas-Nozal M, Hernando V, Vilardosa U, Aluja D, Parra VM, Sanchis D, Garcia-Dorado D (2016) Studies on the role of apoptosis after transient myocardial ischemia: genetic deletion of the executioner caspases-3 and -7 does not limit infarct size and ventricular remodeling. Basic Res Cardiol 111:18. doi:10.1007/s00395-016-0537-6

    Article  PubMed  Google Scholar 

  26. Inserte J, Hernando V, Vilardosa U, Abad E, Poncelas-Nozal M, Garcia-Dorado D (2013) Activation of cGMP/protein kinase G pathway in postconditioned myocardium depends on reduced oxidative stress and preserved endothelial nitric oxide synthase coupling. J Am Heart Assoc 2:e005975. doi:10.1161/JAHA.112.005975

    Article  PubMed  PubMed Central  Google Scholar 

  27. Julien M, Kay RG, Delhanty PJ, Allas S, Granata R, Barton C, Constable S, Ghigo E, van der Lely AJ, Abribat T (2012) In vitro and in vivo stability and pharmacokinetic profile of unacylated ghrelin (UAG) analogues. Eur J Pharm Sci 47:625–635. doi:10.1016/j.ejps.2012.07.014

    Article  CAS  PubMed  Google Scholar 

  28. Khalil H, Peltzer N, Walicki J, Yang JY, Dubuis G, Gardiol N, Held W, Bigliardi P, Marsland B, Liaudet L, Widmann C (2012) Caspase-3 protects stressed organs against cell death. Mol Cell Biol 32:4523–4533. doi:10.1128/MCB.00774-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J (2004) Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62:74–85. doi:10.1016/j.cardiores.2004.01.006

    Article  CAS  PubMed  Google Scholar 

  30. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660. doi:10.1038/45230

    Article  CAS  PubMed  Google Scholar 

  31. Lear PV, Iglesias MJ, Feijoo-Bandin S, Rodriguez-Penas D, Mosquera-Leal A, Garcia-Rua V, Gualillo O, Ghe C, Arnoletti E, Muccioli G, Dieguez C, Gonzalez-Juanatey JR, Lago F (2010) Des-acyl ghrelin has specific binding sites and different metabolic effects from ghrelin in cardiomyocytes. Endocrinology 151:3286–3298. doi:10.1210/en.2009-1205

    Article  CAS  PubMed  Google Scholar 

  32. Li Y, Wang B, Zhou C, Bi Y (2007) Matrine induces apoptosis in angiotensin II-stimulated hyperplasia of cardiac fibroblasts: effects on Bcl-2/Bax expression and caspase-3 activation. Basic Clin Pharmacol Toxicol 101:1–8. doi:10.1111/j.1742-7843.2006.00040.x

    Article  CAS  PubMed  Google Scholar 

  33. Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031

    Article  CAS  PubMed  Google Scholar 

  34. Matsui T, Li L, del Monte F, Fukui Y, Franke TF, Hajjar RJ, Rosenzweig A (1999) Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100:2373–2379

    Article  CAS  PubMed  Google Scholar 

  35. Ng LL, Sandhu JK, Narayan H, Quinn PA, Squire IB, Davies JE, Struck J, Bergmann A, Maisel A, Jones DJ (2014) Pro-substance p for evaluation of risk in acute myocardial infarction. J Am Coll Cardiol 64:1698–1707. doi:10.1016/j.jacc.2014.05.074

    Article  CAS  PubMed  Google Scholar 

  36. Ozcan B, Neggers SJ, Miller AR, Yang HC, Lucaites V, Abribat T, Allas S, Huisman M, Visser JA, Themmen AP, Sijbrands EJ, Delhanty PJ, van der Lely AJ (2014) Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels? Eur J Endocrinol 170:799–807. doi:10.1530/EJE-13-0347

    Article  PubMed  Google Scholar 

  37. Pei XM, Yung BY, Yip SP, Chan LW, Wong CS, Ying M, Siu PM (2015) Protective effects of desacyl ghrelin on diabetic cardiomyopathy. Acta Diabetol 52:293–306. doi:10.1007/s00592-014-0637-4

    Article  CAS  PubMed  Google Scholar 

  38. Pei XM, Yung BY, Yip SP, Ying M, Benzie IF, Siu PM (2014) Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway. Am J Physiol Endocrinol Metab 306:E311–E323. doi:10.1152/ajpendo.00123.2013

    Article  CAS  PubMed  Google Scholar 

  39. Puymirat E, Schiele F, Steg PG, Blanchard D, Isorni MA, Silvain J, Goldstein P, Gueret P, Mulak G, Berard L, Bataille V, Cattan S, Ferrieres J, Simon T, Danchin N, investigators F-M (2014) Determinants of improved one-year survival in non-ST-segment elevation myocardial infarction patients: insights from the French FAST-MI program over 15 years. Int J Cardiol 177:281–286. doi:10.1016/j.ijcard.2014.09.023

    Article  PubMed  Google Scholar 

  40. Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603. doi:10.1016/j.ceb.2005.09.009

    Article  CAS  PubMed  Google Scholar 

  41. Shimada T, Furuta H, Doi A, Ariyasu H, Kawashima H, Wakasaki H, Nishi M, Sasaki H, Akamizu T (2014) Des-acyl ghrelin protects microvascular endothelial cells from oxidative stress-induced apoptosis through sirtuin 1 signaling pathway. Metabolism 63:469–474. doi:10.1016/j.metabol.2013.12.011

    Article  CAS  PubMed  Google Scholar 

  42. Singhal AK, Symons JD, Boudina S, Jaishy B, Shiu YT (2010) Role of endothelial cells in myocardial ischemia-reperfusion injury. Vasc Dis Prev 7:1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stevanovic DM, Grefhorst A, Themmen AP, Popovic V, Holstege J, Haasdijk E, Trajkovic V, van der Lely AJ, Delhanty PJ (2014) Unacylated ghrelin suppresses ghrelin-induced neuronal activity in the hypothalamus and brainstem of male rats [corrected]. PLoS One 9:e98180. doi:10.1371/journal.pone.0098180

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tam BT, Pei XM, Yung BY, Yip SP, Chan LW, Wong CS, Siu PM (2015) Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice. Pflugers Arch 467:2555–2569. doi:10.1007/s00424-015-1721-5

    Article  CAS  PubMed  Google Scholar 

  45. Teixeira G, Abrial M, Portier K, Chiari P, Couture-Lepetit E, Tourneur Y, Ovize M, Gharib A (2013) Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes. J Mol Cell Cardiol 56:55–62. doi:10.1016/j.yjmcc.2012.11.023

    Article  CAS  PubMed  Google Scholar 

  46. Thibault H, Derumeaux G (2008) Assessment of myocardial ischemia and viability using tissue Doppler and deformation imaging: the lessons from the experimental studies. Arch Cardiovasc Dis 101:61–68

    Article  CAS  PubMed  Google Scholar 

  47. Togliatto G, Trombetta A, Dentelli P, Baragli A, Rosso A, Granata R, Ghigo D, Pegoraro L, Ghigo E, Brizzi MF (2010) Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes 59:1016–1025. doi:10.2337/db09-0858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Togliatto G, Trombetta A, Dentelli P, Gallo S, Rosso A, Cotogni P, Granata R, Falcioni R, Delale T, Ghigo E, Brizzi MF (2015) Unacylated ghrelin induces oxidative stress resistance in a glucose intolerance and peripheral artery disease mouse model by restoring endothelial cell miR-126 expression. Diabetes 64:1370–1382. doi:10.2337/db14-0991

    Article  CAS  PubMed  Google Scholar 

  49. von Harsdorf R, Li PF, Dietz R (1999) Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99:2934–2941

    Article  Google Scholar 

  50. Yamaguchi H, Wang HG (2001) The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20:7779–7786. doi:10.1038/sj.onc.1204984

    Article  CAS  PubMed  Google Scholar 

  51. Zeng Z, dos Sarbassov D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109:3509–3512. doi:10.1182/blood-2006-06-030833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. doi:10.1161/CIRCRESAHA.111.249532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang D, Contu R, Latronico MV, Zhang J, Rizzi R, Catalucci D, Miyamoto S, Huang K, Ceci M, Gu Y, Dalton ND, Peterson KL, Guan KL, Brown JH, Chen J, Sonenberg N, Condorelli G (2010) MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 120:2805–2816. doi:10.1172/JCI43008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang G, Yin X, Qi Y, Pendyala L, Chen J, Hou D, Tang C (2010) Ghrelin and cardiovascular diseases. Current Cardiol Rev 6:62–70. doi:10.2174/157340310790231662

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. CarMeN laboratory, INSERM U1060, INRA U1397, Univ Lyon, Université Claude Bernard Lyon1, Groupement Hospitalier Est, Bâtiment B13, 59 boulevard Pinel, Insa-Lyon, 69500, Bron, France

    Rania Harisseh, Bruno Pillot, Abdallah Gharib, Lionel Augeul, Noelle Gallo-Bona, René Ferrera, Joseph Loufouat, Claire Crola Da Silva & Michel Ovize

  2. IHU OPERA, Cardioprotection Laboratory, Hospices Civils de Lyon, CIC, 69500, Bron, France

    Rania Harisseh, Bruno Pillot, Abdallah Gharib, Lionel Augeul, Noelle Gallo-Bona, René Ferrera, Joseph Loufouat, Claire Crola Da Silva & Michel Ovize

  3. Faculté de médecine Lyon Est, Université Lyon 1, 69373, Lyon, France

    Michel Ovize

  4. Service d’Explorations Fonctionnelles Cardiovasculaires et CIC de Lyon, Hôpital Louis Pradel, Hospices Civils de Lyon, 69677, Lyon, France

    Michel Ovize

  5. Alizé Pharma, 69130, Ecully, France

    Thomas Delale, Soraya Allas & Thierry Abribat

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  1. Rania Harisseh
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  2. Bruno Pillot
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Correspondence to Rania Harisseh.

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This project has been supported by grants from the French government’s Fonds unique interministériel (FUI, AAP 14), Région Rhône Alpes, and Grand Lyon, la métropole.

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TD, SA, and TA are employees of Alizé Pharma. TA holds and shares from Alizé Pharma.

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Harisseh, R., Pillot, B., Gharib, A. et al. Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore. Basic Res Cardiol 112, 4 (2017). https://doi.org/10.1007/s00395-016-0595-9

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