Skip to main content
Springer Nature Link
Log in

Cardioprotective effect of ghrelin against myocardial infarction-induced left ventricular injury via inhibition of SOCS3 and activation of JAK2/STAT3 signaling

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

The molecular mechanisms through which ghrelin exerts its cardioprotective effects during cardiac remodeling post-myocardial infarction (MI) are poorly understood. The aim of this study was to investigate whether the cardioprotection mechanisms are mediated by modulation of JAK/STAT signaling and what triggers this modulation. Rats were divided into six groups (n = 12/group): control, sham, sham + ghrelin (100 µg/kg, s.c., daily, starting 1 day post-MI), MI, MI+ ghrelin, and MI+ ghrelin+ AG490, a potent JAK2 inhibitor (5 mg/kg, i.p., daily). All treatments were administered for 3 weeks. Administration of ghrelin to MI rats improved left ventricle (LV) architecture and restored cardiac contraction. In remote non-infarcted areas of MI rats, ghrelin reduced cardiac inflammation and lipid peroxidation and enhanced antioxidant enzymatic activity. In addition, independent of the growth factor/insulin growth factor-1 (GF/IGF-1) axis, ghrelin significantly increased the phosphorylation of JAK2 and Tyr702 and Ser727 residues of STAT3 and inhibited the phosphorylation of JAK1 and Tyr701 and Ser727 residues of STAT1, simultaneously increasing the expression of BCL-2 and decreasing in the expression of BAX, cleaved CASP3, and FAS. This effect coincided with decreased expression of SOCS3. All these beneficial effects of ghrelin, except its inhibitory action on IL-6 expression, were partially and significantly abolished by the co-administration of AG490. In conclusion, the cardioprotective effect of ghrelin against MI-induced LV injury is exerted via activation of JAK2/STAT3 signaling and inhibition of STAT1 signaling. These effects were independent of the GF/IGF-1 axis and could be partially mediated via inhibition of cardiac IL-6.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608. https://doi.org/10.1016/S0092-8674(00)80047-1

    Article  CAS  PubMed  Google Scholar 

  2. Anand I, Ferrari R, Kalra G, Wahi P, Poole-Wilson P, Harris P (1989) Edema of cardiac origin: studies of body water and sodium, renal function, hemodynamic indexes and plasma hormones in untreated congestive cardiac failure. Circulation 80:299–305. https://doi.org/10.1161/01.CIR.80.2.299

    Article  CAS  PubMed  Google Scholar 

  3. Banes AK, Shaw S, Jenkins J, Redd H, Amiri F, Pollock DM, Marrero MB (2004) Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am J Physiol Renal Physiol 286:F653–F659. https://doi.org/10.1152/ajprenal.00163.2003

    Article  CAS  PubMed  Google Scholar 

  4. Banes AK, Shaw SM, Tawfik A, Patel BP, Ogbi S, Fulton D, Marrero MB (2005) Activation of the JAK/STAT pathway in vascular smooth muscle by serotonin. Am J Physiol Cell Physiol 288:C805–C812. https://doi.org/10.1152/ajpcell.00385.2004

    Article  CAS  PubMed  Google Scholar 

  5. 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. https://doi.org/10.1083/jcb.200207165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barry SP, Townsend PA, Latchman DS, Stephanou A (2007) Role of the JAK-STAT pathway in myocardial injury. Trends Mol Med 13:82–89. https://doi.org/10.1016/j.molmed.2006.12.002

    Article  CAS  PubMed  Google Scholar 

  7. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185. https://doi.org/10.1016/j.pharmthera.2008.08.002

    Article  CAS  PubMed  Google Scholar 

  8. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105:771–785. https://doi.org/10.1007/s00395-010-0124-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Booz GW, Day JN, Baker KM (2002) Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. J Mol Cell Cardiol 34:1443–1453. https://doi.org/10.1006/jmcc.2002.2076

    Article  CAS  PubMed  Google Scholar 

  10. Castellano G, Affuso F, Conza PD, Fazio S (2009) The GH/IGF-1 Axis and heart failure. Curr Cardiol Rev 5:203–215. https://doi.org/10.2174/157340309788970306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chang YP, Tsai CC, Huang WC, Wang CY, Chen CL, Lin YS, Kai JI, Hsieh CY, Cheng YL, Choi PC, Chen SH, Chang SP, Liu HS, Lin CF (2010) Autophagy facilitates IFN-c-induced JAK2-STAT1 activation and cellular inflammation. J Biol Chem 285:28715–28722. https://doi.org/10.1074/jbc.M110.133355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chung H, Li E, Kim Y, Kim S, Park S (2013) Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells. J Endocrinol 218:49–59. https://doi.org/10.1530/JOE-13-0045

    Article  CAS  PubMed  Google Scholar 

  13. Cittadini A, Monti MG, Iaccarino G, Castiello MC, Baldi A, Bossone E, Longobardi S, Marra AM, Petrillo V, Saldamarco L, During MJ, Saccà L, Condorelli G (2012) SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway. Cardiovasc Res 96:381–390. https://doi.org/10.1093/cvr/cvs261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Croker BA, Kiu H (2008) Nicholson SE (2008) SOCS: regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19:414–422. https://doi.org/10.1016/j.semcdb.2008.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Das A, Salloum FN, Filippone SM, Durrant DE, Rokosh G, Bolli R, Kukreja RC (2015) Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. Basic Res Cardiol 110:31. https://doi.org/10.1007/s00395-015-0486-5

    Article  PubMed  Google Scholar 

  16. Dorn GW (2009) Novel pharmacotherapies to abrogate postinfarction ventricular remodeling. Nat Rev Cardiol 6:283–291. https://doi.org/10.1038/nrcardio.2009.12

    Article  CAS  PubMed  Google Scholar 

  17. El-Adawi H, Deng L, Tramontano A, Smith S, Mascareno E, Ganguly K, Castillo R, El-Sherif N (2003) The functional role of the JAK-STAT pathway in post-infarction remodeling. Cardiovasc Res 57:129–138. https://doi.org/10.1016/S0008-6363(02)00614-4

    Article  CAS  PubMed  Google Scholar 

  18. Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102:393–4115. https://doi.org/10.1007/s00395-007-0674-z

    Article  CAS  PubMed  Google Scholar 

  19. Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R (2003) Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 98:401–405. https://doi.org/10.1007/s00395-003-0434-7

    Article  CAS  PubMed  Google Scholar 

  20. Friberg L, Werner S, Eggertsen G, Ahnve S (2000) Growth hormone and insulin-like growth factor-1 in acute myocardial infarction. Eur Heart J 21:1547–1554. https://doi.org/10.1053/euhj.2000.2125

    Article  CAS  PubMed  Google Scholar 

  21. Fuglesteg BN, Suleman N, Tiron C, Kanhema T, Lacerda L, Andreasen TV, Sack MN, Jonassen AK, Mjøs OD, Opie LH, Lecour S (2008) Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion. Basic Res Cardiol 103:444–453. https://doi.org/10.1007/s00395-008-0728-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gedik N, Kottenberg E, Thielmann M, Frey UH, Jakob H, Peters J, Heusch G, Kleinbongard P (2017) Potential humoral mediators of remote ischemic preconditioning in patients undergoing surgical coronary revascularization. Sci Rep. https://doi.org/10.1038/s41598-017-12833

    Google Scholar 

  23. Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R (2006) Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Invest 29:115–121. https://doi.org/10.1007/BF03344083

    Article  CAS  PubMed  Google Scholar 

  24. Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, Ohtsuka M, Matsuura K, Sano M, Nishi J, Iwanaga K, Akazawa H, Kunieda T, Zhu W, Hasegawa H, Kunisada K, Nagai T, Nakaya H, Yamauchi-Takihara K, Komuro I (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the JAK-STAT pathway in cardiomyocytes. Nat Med 11:305–311. https://doi.org/10.1038/nm1199

    Article  CAS  PubMed  Google Scholar 

  25. Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T, Imanaka-Yoshida K, Itoh T, Takeshita A (2003) Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol 285(3):H1229–H1235. https://doi.org/10.1152/ajpheart.00207.2003

    Article  CAS  PubMed  Google Scholar 

  26. Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. https://doi.org/10.1161/CIRCRESAHA.111.255604

    Article  CAS  PubMed  Google Scholar 

  27. Higuchi T, Yamauchi-Takihara K, Matsumiya G, Fukushima N, Ichikawa H, Kuratani T, Maehata Y, Sawa Y (2008) Granulocyte colony-stimulating factor prevents reperfusion injury after heart preservation. Ann Thorac Surg 85:1367–1373. https://doi.org/10.1016/j.athoracsur.2007.12.053

    Article  PubMed  Google Scholar 

  28. Hilfiker-Kleiner D, Hilfiker A, Drexler H (2005) Many good reasons to have STAT3 in the heart. Pharmacol Ther 107:131–137. https://doi.org/10.1016/j.pharmthera.2005.02.003

    Article  CAS  PubMed  Google Scholar 

  29. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, Podewski E, Poli V, Schneider MD, Schulz R, Park JK, Wollert KC, Drexler H (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95:187–195. https://doi.org/10.1161/01.RES.0000134921.50377.61

    Article  CAS  PubMed  Google Scholar 

  30. Hong F, Jaruga B, Kim WH, Radaeva S, El-Assal ON, Tian Z, Nguyen VA, Gao B (2002) Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest 110:1503–1513. https://doi.org/10.1172/JCI15841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang CH, Tsai MS, Chiang CY, Su YJ, Wang TD, Chang WT, Chen HW, Chen WJ (2015) Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction. Basic Res Cardiol 110:59. https://doi.org/10.1007/s00395-015-0516-3

    Article  PubMed  Google Scholar 

  32. Isgaard J, Arcopinto M, Karason K, Cittadini A (2015) GH and the cardiovascular system: an update on a topic at heart. Endocrine 48:25–35. https://doi.org/10.1007/s12020-014-0327-6

    Article  CAS  PubMed  Google Scholar 

  33. Izumi M, Masaki M, Hiramoto Y, Sugiyama S, Kuroda T, Terai K, Hori M, Kawase I, Hirota H (2006) Cross-talk between bone morphogenetic protein 2 and leukemia inhibitory factor through ERK 1/2 and Smad1 in protection against doxorubicin induced injury of cardiomyocytes. J Mol Cell Cardiol 40:224–233. https://doi.org/10.1016/j.yjmcc.2005.11.007

    Article  CAS  PubMed  Google Scholar 

  34. Kishore R, Verma SK (2012) Roles of STATs signaling in cardiovascular diseases. JAK-STAT 1:118–124. https://doi.org/10.4161/jkst.20115

    Article  PubMed  PubMed Central  Google Scholar 

  35. Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R (2009) IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 104:e9–e18. https://doi.org/10.1161/CIRCRESAHA.108.188243

    Article  CAS  PubMed  Google Scholar 

  36. Knight RA, Scarabelli Tiziano M, Anastasis S (2012) STAT transcription in the ischemic heart. JAK-STAT 1:111–117. https://doi.org/10.4161/jkst.20078

    Article  PubMed  PubMed Central  Google Scholar 

  37. Latchman DS, Stephanou A (2012) STAT1 deficiency in the heart protects against myocardial infarction by enhancing autophagy. J Cell Mol Med 16:386–393. https://doi.org/10.1111/j.1582-4934.2011.01323.x

    Article  PubMed  PubMed Central  Google Scholar 

  38. Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662. https://doi.org/10.1038/nrm909

    Article  CAS  PubMed  Google Scholar 

  39. Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C (2012) Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS ONE 7:e35265. https://doi.org/10.1371/journal.pone.0035265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mascareno E, El-Shafei M, Maulik N, Sato M, Guo Y, Das DK, Siddiqui MA (2001) JAK/STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion. Circulation 104:325–329. https://doi.org/10.1161/01.CIR.104.3.325

    Article  CAS  PubMed  Google Scholar 

  41. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M (2002) Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 40:694–699. https://doi.org/10.1161/01.hyp.0000035395.51441.10

    Article  CAS  PubMed  Google Scholar 

  42. McCormick J, Barry SP, Sivarajah A, Stefanutti G, Townsend PA, Lawrence KM, Eaton S, Knight RA, Thiemermann C, Latchman DS, Stephanou A (2006) Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J 20:2115–2117. https://doi.org/10.1096/fj.06-6188fje

    Article  CAS  PubMed  Google Scholar 

  43. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, Ueno K, Kitakaze M, Miyatake K, Kangawa K (2004) Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 110:3674–3679. https://doi.org/10.1161/01.CIR.0000149746.62908.BB

    Article  CAS  PubMed  Google Scholar 

  44. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K (2001) Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 104:1430–1435. https://doi.org/10.1161/hc3601.095575

    Article  CAS  PubMed  Google Scholar 

  45. Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, Osugi T, Izumi M, Oshima Y, Nakaoka Y, Hirota H, Kishimoto T, Yamauchi-Takihara K (2001) Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–981. https://doi.org/10.1161/hc3401.095947

    Article  CAS  PubMed  Google Scholar 

  46. Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, Yamauchi-Takihara K (2000) Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res 47:797–805. https://doi.org/10.1016/S0008-6363(00)00138-3

    Article  CAS  PubMed  Google Scholar 

  47. Oshima Y, Fujio Y, Nakanishi T, Itoh N, Yamamoto Y, Negoro S, Tanaka K, Kishimoto T, Kawase I, Azuma J (2005) STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc Res 65:428–435. https://doi.org/10.1016/j.cardiores.2004.10.021

    Article  CAS  PubMed  Google Scholar 

  48. Omura T, Yoshiyama M, Ishikura F, Kobayashi H, Takeuchi K, Beppu S, Yoshikawa J (2001) Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats. J Mol Cell Cardiol 33:307–316. https://doi.org/10.1006/jmcc.2000.1303

    Article  CAS  PubMed  Google Scholar 

  49. Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, Izumi M, Nakaoka Y, Hirota H, Okabe M, Yamauchi-Takihara K, Kawase I, Kishimoto T (2002) Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart. J Biol Chem 277:6676–6681. https://doi.org/10.1074/jbc.M108246200

    Article  CAS  PubMed  Google Scholar 

  50. Pedretti S, Raddatz E (2011) STAT3a interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart. Basic Res Cardiol 106:355–369. https://doi.org/10.1007/s00395-011-0152-5

    Article  CAS  PubMed  Google Scholar 

  51. 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. https://doi.org/10.1152/ajpendo.00123.2013

    Article  CAS  PubMed  Google Scholar 

  52. Pemberton C, Wimalasena P, Yandle T, Soule S, Richards M (2003) C-terminal pro-ghrelin peptides are present in the human circulation. Biochem Biophys Res Commun 310:567–573. https://doi.org/10.1016/j.bbrc.2003.09.045

    Article  CAS  PubMed  Google Scholar 

  53. Pezet A, Favre H, Kelly PA, Edery M (1999) Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling. J Biol Chem 274:24497–24502. https://doi.org/10.1074/jbc.274.35

    Article  CAS  PubMed  Google Scholar 

  54. Podewski EK, Hilfiker-Kleiner D, Hilfiker A, Morawietz H, Lichtenberg A, Wollert KC, Drexler H (2003) Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation 107:798–802. https://doi.org/10.1161/01.CIR.0000057545.82749

    Article  CAS  PubMed  Google Scholar 

  55. Qin F, Liang MC, Liang CS (2005) Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits. Biochim Biophys Acta 1740:499–513. https://doi.org/10.1016/j.bbadis.2004.11.007

    Article  CAS  PubMed  Google Scholar 

  56. Qing Y, Stark GR (2004) Alternative activation of STAT1 and STAT3 in response to interferon-γ. J Biol Chem 279:41679–41685. https://doi.org/10.1074/jbc.M406413200

    Article  CAS  PubMed  Google Scholar 

  57. Ram PA, Park SH, Choi HK, Waxman DJ (1996) Growth Hormone Activation of Stat 1, Stat 3, and Stat 5 in Rat Liver. Differential kinetics of hormone desensitization and growth hormone stimulation of both tyrosine phosphorylation and serine/threonine phosphorylation. J Biol Chem 271:5929–5940. https://doi.org/10.1074/jbc.271.10.5929

    Article  CAS  PubMed  Google Scholar 

  58. Scarabelli TM, Gottlieb RA (2004) Functional and clinical repercussions of myocyte apoptosis in the multifaceted damage by ischemia/reperfusion injury: old and new concepts after 10 years of contributions. Cell Death Differ 11:S144–S152. https://doi.org/10.1038/sj.cdd.4401544

    Article  CAS  PubMed  Google Scholar 

  59. Sivaraman V, Yellon DM (2014) Pharmacologic therapy that simulates conditioning for cardiac ischemic/reperfusion injury. J Cardiovasc Pharmacol Ther 19:83–96. https://doi.org/10.1177/1074248413499973

    Article  CAS  PubMed  Google Scholar 

  60. Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, Davidson SM, Hausenloy DJ, Yellon DM (2010) Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 299:H1265–H1270. https://doi.org/10.1152/ajpheart.00092.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Soeki T, Kishimoto I, Schwenke DO, Tokudome T, Horio T, Yoshida M, Hosoda H, Kangawa K (2008) Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 294:H426–H432. https://doi.org/10.1152/ajpheart.00643.2007

    Article  CAS  PubMed  Google Scholar 

  62. Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS (2001) Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem 276:28340–28347. https://doi.org/10.1074/jbc.M101177200

    Article  CAS  PubMed  Google Scholar 

  63. Stephanou A, Brar BK, Knight RA, Latchman DS (2000) Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ 7:329–330. https://doi.org/10.1038/sj.cdd.4400656

    Article  CAS  PubMed  Google Scholar 

  64. Stephanou A, Brar BK, Scarabelli TM, Jonassen AK, Yellon DM, Marber MS, Knight RA, Latchman DS (2000) Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem 275:10002–10008. https://doi.org/10.1074/jbc.275.14.10002

    Article  CAS  PubMed  Google Scholar 

  65. Szczepanek K, Chen Q, Larner AC, Lesnefsky EJ (2012) Cytoprotection by the modulation of mitochondrial electron transport chain: the emerging role of mitochondrial STAT3. Mitochondrion 12:180–189. https://doi.org/10.1016/j.mito.2011.08.011

    Article  CAS  PubMed  Google Scholar 

  66. Takahashi T, Fukuda K, Pan J, Kodama H, Sano M, Makino S, Kato T, Manabe T, Ogawa S (1999) Characterization of Insulin-Like Growth Factor-1–Induced Activation of the JAK/STAT Pathway in Rat Cardiomyocytes. Circ Res 85:884–891. https://doi.org/10.1161/01.RES.85.10884

    Article  CAS  PubMed  Google Scholar 

  67. Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C (2010) Metabolic and cardiovascular effects of ghrelin. Curr Diabetes Rev 6:228–253. https://doi.org/10.2174/157339910791658871

    Article  CAS  PubMed  Google Scholar 

  68. Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A (2004) STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem 279:5811–5820. https://doi.org/10.1074/jbc.M302637200

    Article  CAS  PubMed  Google Scholar 

  69. Townsend PA, Scarabelli TM, Pasini E, Gitti G, Menegazzi M, Suzuki H, Knight RA, Latchman DS, Stephanou A (2004) Epigallocatechin-3-gallate inhibits STAT- 1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis. FASEB J 18:1621–1623. https://doi.org/10.1096/fj.04-1716fje

    Article  CAS  PubMed  Google Scholar 

  70. Wakabayashi H, Taki J, Inaki A, Shiba K, Matsunari I, Kinuya S (2015) Correlation between apoptosis and left ventricular remodeling in subacute phase of myocardial ischemia and reperfusion. EJNMMI Res 5–11:72. https://doi.org/10.1186/s13550-015-0152-9

    Article  Google Scholar 

  71. Wang Q, Lin P, Li P, Feng L, Ren Q, Xie X, Xu J (2017) Ghrelin protects the heart against ischemia/reperfusion injury via inhibition of TLR4/NLRP3 inflammasome pathway. Life Sci 1(186):50–58. https://doi.org/10.1016/j.lfs.2017.08.004

    Article  Google Scholar 

  72. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323:793–797. https://doi.org/10.1126/science.1164551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wiley KE, Davenport AP (2002) Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 136:1146–1152. https://doi.org/10.1038/sj.bjp.0704815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xuan YT, Guo Y, Han H, Zhu Y, Bolli R (2001) An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc Natl Acad Sci USA 98:9050–9055. https://doi.org/10.1073/pnas.161283798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang C, Liu Z, Liu K, Yang P (2014) Mechanisms of ghrelin anti-heart failure: inhibition of Ang II induced cardiomyocyte apoptosis by down-regulating AT1R expression. PLoS ONE 9:e85785. https://doi.org/10.1371/journal.pone.0085785

    Article  PubMed  PubMed Central  Google Scholar 

  76. Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, Wang F, Li Y, Yu X (2008) Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rats. Nephrol Dial Transplant 23:91–100. https://doi.org/10.1093/ndt/gfm509

    Article  CAS  PubMed  Google Scholar 

  77. Yasukawa H, Nagata T, Oba T, Imaizumi T (2012) SOCS3: a novel therapeutic target for cardioprotection. JAK-STAT 1:234–240. https://doi.org/10.4161/jkst.22435

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zgheib C, Zouein FA, Kurdi M, Booz GW (2012) Differential STAT3 signaling in the heart impact of concurrent signals and oxidative stress. JAK-STAT 1:101–110. https://doi.org/10.4161/jkst.19776

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH (2000) Mechanism of STAT3 activation by insulin-like growth factor 1 receptor. J Biol Chem 275:15099–15105. https://doi.org/10.1074/jbc.M000089200

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the deanship of the scientific research at King Khalid University for financially supporting this study and the technical staff of the animal house facility at the College pharmacy at King Saud University for their help in the study. They also would like to thank others who provided technical support.

Funding

This research was fully funded by the scientific research at King Khalid University.

Author information

Authors and Affiliations

  1. Department of Pathology, College of Medicine, King Khalid University, Abha, 61421, Saudi Arabia

    Refaat A. Eid & Mubarak Al-Shraim

  2. Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 14611, Saudi Arabia

    Mahmoud A. Alkhateeb & Hussain Aldera

  3. College of Health Sciences, Applied Medical Sciences Department, PAAET, Shuwaikh, Kuwait

    Samy Eleawa

  4. Department of Physiology, College of Medicine, King Khalid University, P.O. Box 641, Abha, 61421, Saudi Arabia

    Fahaid H. Al-Hashem & Mohammad A. Dallak

  5. Department of Biology, College of Science, King Khalid University, P.O. Box 641, Abha, 61421, Saudi Arabia

    Attalla Farag El-kott

  6. Department of Anatomy, College of Medicine, King Khalid University, P.O. Box 641, Abha, 61421, Saudi Arabia

    Mohamed Samir Ahmed Zaki

Authors
  1. Refaat A. Eid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud A. Alkhateeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samy Eleawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fahaid H. Al-Hashem
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mubarak Al-Shraim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Attalla Farag El-kott
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohamed Samir Ahmed Zaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammad A. Dallak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hussain Aldera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Refaat A. Eid.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eid, R.A., Alkhateeb, M.A., Eleawa, S. et al. Cardioprotective effect of ghrelin against myocardial infarction-induced left ventricular injury via inhibition of SOCS3 and activation of JAK2/STAT3 signaling. Basic Res Cardiol 113, 13 (2018). https://doi.org/10.1007/s00395-018-0671-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-018-0671-4

Keywords

Search

Navigation