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Ghrelin protects the heart against ischemia-induced arrhythmias by preserving connexin-43 protein

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Abstract

Vagal nerve stimulation has been postulated to confer an antifibrillatory effect. We studied whether ghrelin administration would exert an antiarrhythmic effect via modulation of autonomic nerve activity in rats after acute myocardial ischemia (MI). Male Sprague-Dawley rats were exposed to 30 min of ischemia following ligation of the left coronary artery. Animals were then randomized to receive either ghrelin (n = 26) or saline (n = 26) during the period of coronary ligation. Power spectral analysis of heart-rate variability revealed that the administration of ghrelin increased the high-frequency (HF) power and decreased the low-frequency (LF)/HF ratio. Ventricular tachyarrhythmias were less frequent in rats after MI who received ghrelin in comparison with rats that received saline. Immunoblotting and immunohistochemistry revealed that rats given saline alone during MI exhibited a marked reduction in phosphorylated connexin-43 within the left ventricle, whereas those that received ghrelin displayed only minor reductions in comparison with sham-operated rats. These effects of ghrelin were diminished by the coadministration of atropine or the blockade of vagal afferents. These data demonstrate that the beneficial effect of ghrelin might be mediated by modulation of cardiac autonomic nerve activity.

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References

  1. 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

    Article  PubMed  CAS  Google Scholar 

  2. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    Article  PubMed  CAS  Google Scholar 

  3. Kishimoto I, Tokudome T, Schwenke DO, Soeki T, Hosoda H, Nagaya N, Kangawa K (2009) Therapeutic potential of ghrelin in cardiac diseases. Expert Rev Endocrinol Metab 4:283–289

    Article  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. Schwenke DO, Tokudome T, Kishimoto I, Horio T, Shirai M, Cragg PA, Kangawa K (2008) Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Endocrinology 149:5172–5176

    Article  PubMed  CAS  Google Scholar 

  6. Sternick EB, Piorkowski C, Hindricks G, Dagres N, Sommer P (2011) Electrical storm originating from a left ventricular epicardial scar in a patient with completely normal endocardial voltage. Heart Vessels 26:663–666

    Article  PubMed  Google Scholar 

  7. Abulaiti A, Hu D, Zhu D, Zhang R (2011) Influence of fastigial nucleus stimulation on heart rate variability of surgically induced myocardial infarction rats: fastigial nucleus stimulation and autonomous nerve activity. Heart Vessels 26:654–662

    Article  PubMed  Google Scholar 

  8. Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T (2005) Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation 112:164–170

    Article  PubMed  CAS  Google Scholar 

  9. Jiang H, Hu X, Lu Z, Wen H, Zhao D, Tang Q, Yang B (2008) Effects of sympathetic nerve stimulation on ischemia-induced ventricular arrhythmias by modulating connexin43 in rats. Arch Med Res 39:647–654

    Article  PubMed  CAS  Google Scholar 

  10. Roell W, Lewalter T, Sasse P, Tallini YN, Choi BR, Breitbach M, Doran R, Becher UM, Hwang SM, Bostani T, von Maltzahn J, Hofmann A, Reining S, Eiberger B, Gabris B, Pfeifer A, Welz A, Willecke K, Salama G, Schrickel JW, Kotlikoff MI, Fleischmann BK (2007) Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450:819–824

    Article  PubMed  CAS  Google Scholar 

  11. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120–1128

    Article  PubMed  CAS  Google Scholar 

  12. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M (2002) Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 40:694–699

    Article  PubMed  CAS  Google Scholar 

  13. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M (2004) Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 43:977–982

    Article  PubMed  CAS  Google Scholar 

  14. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ (1991) Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 68:1471–1481

    Article  PubMed  CAS  Google Scholar 

  15. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K (2004) Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 109:120–124

    Article  PubMed  Google Scholar 

  16. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kléber AG, Schuessler RB, Saffitz JE (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    Article  PubMed  CAS  Google Scholar 

  17. Lerner DL, Yamada KA, Schuessler RB, Saffitz JE (2000) Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101:547–552

    Article  PubMed  CAS  Google Scholar 

  18. Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339

    Article  PubMed  CAS  Google Scholar 

  19. van Koppen CJ, Kaiser B (2003) Regulation of muscarinic acetylcholine receptor signaling. Pharmacol Ther 98:197–220

    Article  PubMed  Google Scholar 

  20. Liu H, McPherson BC, Zhu X, Da Costa ML, Jeevanandam V, Yao Z (2001) Role of nitric oxide and protein kinase C in ACh-induced cardioprotection. Am J Physiol Heart Circ Physiol 281:H191–H197

    PubMed  CAS  Google Scholar 

  21. Shimada M, Terada T (2002) Roles of cAMP in regulation of both MAP kinase and p34(cdc2) kinase activity during meiotic progression, especially beyond the MI stage. Mol Reprod Dev 62:124–131

    Article  PubMed  CAS  Google Scholar 

  22. Hervé JC, Plaisance I, Loncarek J, Duthe F, Sarrouilhe D (2004) Is the junctional uncoupling elicited in rat ventricular myocytes by some dephosphorylation treatments due to changes in the phosphorylation status of Cx43? Eur Biophys J 33:201–210

    Article  PubMed  Google Scholar 

  23. Lampe PD, Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol 36:1171–1186

    Article  PubMed  CAS  Google Scholar 

  24. Nagaya N, Kangawa K (2003) Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 3:146–151

    Article  PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. Iglesias MJ, Pineiro R, Blanco M, Gallego R, Dieguez C, Gualillo O, Gonzalez-Juanatey JR, Lago F (2004) Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res 62:481–488

    Article  PubMed  CAS  Google Scholar 

  27. Chang L, Ren Y, Liu X, Li WG, Yang J, Geng B, Weintraub NL, Tang C (2004) Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 43:165–170

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Kazue Ishikawa for her assistance and contributions to the study. This study was supported by research grants from the Japan Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Scientific Research (C) [JSPS (C)-21590899]. All authors have reported that they have no relationships to disclose relevant to the content of this article.

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Correspondence to Takeshi Soeki.

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Soeki, T., Niki, T., Uematsu, E. et al. Ghrelin protects the heart against ischemia-induced arrhythmias by preserving connexin-43 protein. Heart Vessels 28, 795–801 (2013). https://doi.org/10.1007/s00380-013-0333-2

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  • DOI: https://doi.org/10.1007/s00380-013-0333-2

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