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Protective effects of desacyl ghrelin on diabetic cardiomyopathy

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Abstract

Aim

Diabetic cardiomyopathy is a specific complication of type 2 diabetes mellitus, which causes progressive cardiac dysfunction. Desacyl ghrelin has been preliminarily demonstrated to have beneficial effects on cardiovascular system and glucose metabolism, which are both related to diabetic cardiomyopathy. The aim of this study was to investigate the protective effects of desacyl ghrelin on cardiac dysfunction, cardiac fibrosis, and cellular autophagy in a type 2 diabetic mouse model.

Materials and methods

Fourteen- to eighteen-week-old db/db diabetic and db/+ non-diabetic mice were intraperitoneally treated with desacyl ghrelin at a dosage of 100 μg/kg for ten consecutive days. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography.

Results

The presence of diabetic cardiomyopathy was evident by the reduction in fractional shortening shown in our examined db/db mice. Intriguingly, this reduction in fractional shortening was not observed in the hearts of db/db mice treated with desacyl ghrelin. Cardiac fibrosis (indicated by excessive collagen deposition, decreased by Adiponectin and Mmp13 expression, and up-regulated by Mmp8 expression) and impairment of autophagic signalling (indicated by decreases in Foxo3 and LC3 II-to-LC3 I ratio) were shown in the hearts of diabetic mice. All these cellular and molecular alterations were alleviated by desacyl ghrelin treatment. The key cardiac pro-survival cellular signals including AMPK, Akt, ERK1/2, and GSK3α/β were impaired in the diabetic hearts, but the administration of desacyl ghrelin attenuated these signalling impairments.

Conclusions

These results collectively demonstrate that desacyl ghrelin protects the heart against cardiac dysfunction in type 2 diabetic mice by inhibiting excessive collagen deposition and enhancing cardiac autophagic signalling via the pro-survival cellular AMPK/ERK1/2 signalling pathways.

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References

  1. Voulgari C, Papadogiannis D, Tentolouris N (2010) Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies. Vasc Health Risk Manag 6:883–903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30:595–602

    Article  CAS  PubMed  Google Scholar 

  3. Hosoda H, Kojima M, Matsuo H, Kangawa K (2000) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279:909–913

    Article  CAS  PubMed  Google Scholar 

  4. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132:387–396

    Article  CAS  PubMed  Google Scholar 

  5. Gutierrez JA, Solenberg PJ, Perkins DR et al (2008) Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 105:6320–6325

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. van der Lely AJ, Tschop M, Heiman ML, Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426–457

    Article  PubMed  Google Scholar 

  7. Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C (2010) Cardiovascular and metabolic effects of ghrelin. Curr Diabetes Rev 6:228–235

    Article  CAS  PubMed  Google Scholar 

  8. Baldanzi G, Filigheddu N, Cutrupi S et al (2002) Ghrelin and desacyl 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 Central  CAS  PubMed  Google Scholar 

  9. Nagaya N, Uematsu M, Kojima M et al (2001) Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 104:1430–1435

    Article  CAS  PubMed  Google Scholar 

  10. Aoki H, Nakata M, Dezaki K et al (2013) Ghrelin counteracts salt-induced hypertension via promoting diuresis and renal nitric oxide production in Dahl rats. Endocr J 60:571–581

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  PubMed Central  PubMed  Google Scholar 

  13. Isgaard J, Granata R (2011) Ghrelin in cardiovascular disease and atherogenesis. Mol Cell Endocrinol 340:59–64

    Article  CAS  PubMed  Google Scholar 

  14. Rodriguez A, Gomez-Ambrosi J, Catalan V et al (2010) Association of plasma acylated ghrelin with blood pressure and left ventricular mass in patients with metabolic syndrome. J Hypertens 28:560–567

    Article  CAS  PubMed  Google Scholar 

  15. Broglio F, Arvat E, Benso A et al (2001) Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86:5083–5086

    Article  CAS  PubMed  Google Scholar 

  16. Barazzoni R, Bosutti A, Stebel M et al (2005) Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab 288:E228–E235

    Article  CAS  PubMed  Google Scholar 

  17. Tsubone T, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H (2005) Ghrelin regulates adiposity in white adipose tissue and UCP1 mRNA expression in brown adipose tissue in mice. Regul Pept 130:97–103

    Article  CAS  PubMed  Google Scholar 

  18. Miegueu P, St Pierre D, Broglio F, Cianflone K (2011) Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes. J Cell Biochem 112:704–714

    Article  CAS  PubMed  Google Scholar 

  19. Muccioli G, Pons N, Ghe C, Catapano F, Granata R, Ghigo E (2004) Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 498:27–35

    Article  CAS  PubMed  Google Scholar 

  20. Rodriguez A, Gomez-Ambrosi J, Catalan V et al (2009) Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes (Lond) 33:541–552

    Article  CAS  Google Scholar 

  21. Davies JS, Kotokorpi P, Eccles SR et al (2009) Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention. Mol Endocrinol 23:914–924

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Delhanty PJ, Huisman M, Baldeon-Rojas LY et al (2013) Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. FASEB J 27:1690–1700

    Article  CAS  PubMed  Google Scholar 

  23. Granata R, Settanni F, Julien M et al (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

    Article  CAS  PubMed  Google Scholar 

  24. Delhanty PJ, Neggers SJ, van der Lely AJ (2014) Should we consider des-acyl ghrelin as a separate hormone and if so, what does it do? Front Horm Res 42:163–174

    Article  PubMed  Google Scholar 

  25. Li L, Zhang LK, Pang YZ et al (2006) Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats. Acta Pharmacol Sin 27:527–535

    Article  PubMed  Google Scholar 

  26. Siu PM, Bae S, Bodyak N, Rigor DL, Kang PM (2007) Response of caspase-independent apoptotic factors to high salt diet-induced heart failure. J Mol Cell Cardiol 42:678–686

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Lang RM, Bierig M, Devereux RB et al (2006) Recommendations for chamber quantification. Eur J Echocardiogr 7:79–108

    Article  PubMed  Google Scholar 

  28. Dittoe N, Stultz D, Schwartz BP, Hahn HS (2007) Quantitative left ventricular systolic function: from chamber to myocardium. Crit Care Med 35:S330–S339

    Article  PubMed  Google Scholar 

  29. Siu PM, Bryner RW, Martyn JK, Alway SE (2004) Apoptotic adaptations from exercise training in skeletal and cardiac muscles. FASEB J 18:1150–1152

    CAS  PubMed  Google Scholar 

  30. Siu PM, Bryner RW, Murlasits Z, Alway SE (2005) Response of XIAP, ARC, and FLIP apoptotic suppressors to 8 wk of treadmill running in rat heart and skeletal muscle. J Appl Physiol 99:204–209

    Article  CAS  PubMed  Google Scholar 

  31. Aasum E, Hafstad AD, Severson DL, Larsen TS (2003) Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes 52:434–441

    Article  CAS  PubMed  Google Scholar 

  32. Lear PV, Iglesias MJ, Feijoo-Bandin S et al (2010) Des-acyl ghrelin has specific binding sites and different metabolic effects from ghrelin in cardiomyocytes. Endocrinology 151:3286–3298

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. Huynh K, Kiriazis H, Du XJ et al (2012) Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes. Diabetologia 55:1544–1553

    Article  CAS  PubMed  Google Scholar 

  35. Marra F, Navari N, Vivoli E, Galastri S, Provenzano A (2011) Modulation of liver fibrosis by adipokines. Dig Dis 29:371–376

    PubMed  Google Scholar 

  36. Kwon EY, Shin SK, Cho YY et al (2012) Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity. BMC Genom 13:450

    Article  CAS  Google Scholar 

  37. Yi W, Sun Y, Yuan Y et al (2012) C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart. Circulation 125:3159–3169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Caligiuri A, Bertolani C, Guerra CT et al (2008) Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 47:668–676

    Article  CAS  PubMed  Google Scholar 

  39. Subramaniam N, Sherman MH, Rao R et al (2012) Metformin-mediated Bambi expression in hepatic stellate cells induces prosurvival Wnt/beta-catenin signaling. Cancer Prev Res (Phila) 5:553–561

    Article  CAS  Google Scholar 

  40. Essick EE, Ouchi N, Wilson RM et al (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301:H984–H993

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Shibata R, Ouchi N, Ito M et al (2004) Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384–1389

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Khatwa UA, Kleibrink BE, Shapiro SD, Subramaniam M (2010) MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis. J Leukoc Biol 87:69–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF Jr (1996) Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross-links. Am J Pathol 148:1639–1648

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Craig VJ, Quintero PA, Fyfe SE et al (2013) Profibrotic activities for matrix metalloproteinase-8 during bleomycin-mediated lung injury. J Immunol 190:4283–4296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Wilson KD, Li Z, Wagner R et al (2008) Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality. PLoS ONE 3:e2609

    Article  PubMed Central  PubMed  Google Scholar 

  46. Takatsu H, Duncker CM, Arai M, Becker LC (1999) Granulocyte accumulation in ischemic/reperfused myocardium: assessment with a technetium-99 m-labeled antigranulocyte monoclonal antibody in the dog. J Nucl Cardiol 6:641–650

    Article  CAS  PubMed  Google Scholar 

  47. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87:1285–1342

    Article  CAS  PubMed  Google Scholar 

  48. Shimizu M, Umeda K, Sugihara N et al (1993) Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol 46:32–36

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Xie Z, Lau K, Eby B et al (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60:1770–1778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Marsh SA, Powell PC, Dell’italia LJ, Chatham JC (2013) Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart. Life Sci 92:648–656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Rodriguez A, Gomez-Ambrosi J, Catalan V et al (2012) The ghrelin O-acyltransferase-ghrelin system reduces TNF-alpha-induced apoptosis and autophagy in human visceral adipocytes. Diabetologia 55:3038–3050

    Article  CAS  PubMed  Google Scholar 

  52. Slupecka M, Wolinski J, Pierzynowski SG (2012) The effects of enteral ghrelin administration on the remodeling of the small intestinal mucosa in neonatal piglets. Regul Pept 174:38–45

    Article  CAS  PubMed  Google Scholar 

  53. Yu AP, Pei XM, Sin TK, Yip SP, Yung BY, Chan LW, Wong CS, Siu PM (2014) Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle. Acta Physiol (Oxf) 211:201–213

    Article  CAS  Google Scholar 

  54. Sengupta A, Molkentin JD, Yutzey KE (2009) FoxO transcription factors promote autophagy in cardiomyocytes. J Biol Chem 284:28319–28331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Mammucari C, Schiaffino S, Sandri M (2008) Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4:524–526

    Article  CAS  PubMed  Google Scholar 

  56. Schips TG, Wietelmann A, Hohn K et al (2011) FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res 91:587–597

    Article  CAS  PubMed  Google Scholar 

  57. Xie Z, He C, Zou MH (2011) AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. Autophagy 7:1254–1255

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. El MS, Rongen GA, Riksen NP (2013) Metformin therapy in diabetes: the role of cardioprotection. Curr Atheroscler Rep 15:314

    Article  Google Scholar 

  59. Favaro E, Granata R, Miceli I et al (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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Baragli A, Ghe C, Arnoletti E, Granata R, Ghigo E, Muccioli G (2011) Acylated and unacylated ghrelin attenuate isoproterenol-induced lipolysis in isolated rat visceral adipocytes through activation of phosphoinositide 3-kinase gamma and phosphodiesterase 3B. Biochim Biophys Acta 1811:386–396

    Article  CAS  PubMed  Google Scholar 

  61. Wong WR, Chen YY, Yang SM, Chen YL, Horng JT (2005) Phosphorylation of PI3 K/Akt and MAPK/ERK in an early entry step of enterovirus 71. Life Sci 78:82–90

    Article  CAS  PubMed  Google Scholar 

  62. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by The Hong Kong Polytechnic University. The authors acknowledge the animal husbandry support received from the Centralised Animal Facilities of The Hong Kong Polytechnic University.

Conflict of interest

Xiao M. Pei, Benjamin Y. Yung, Shea P. Yip, Lawrence W. Chan, Cesar S. Wong, Michael Ying, and Parco M. Siu declare that they have no conflict of interest.

Ethical standard

All experimental procedures related to animal handling in the present study were adhered to the approval obtained from the Animal Subjects Ethics Subcommittee of The Hong Kong Polytechnic University.

Human and animal rights

This article does not contain any studies with human subjects performed by any of the authors. All institutional and national guidelines for the care and use of laboratory animals were followed.

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Authors and Affiliations

  1. Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

    Xiao M. Pei, Benjamin Y. Yung, Shea P. Yip, Lawrence W. Chan, Cesar S. Wong, Michael Ying & Parco M. Siu

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  1. Xiao M. Pei
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  2. Benjamin Y. Yung
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Correspondence to Parco M. Siu.

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Pei, X.M., Yung, B.Y., Yip, S.P. et al. Protective effects of desacyl ghrelin on diabetic cardiomyopathy. Acta Diabetol 52, 293–306 (2015). https://doi.org/10.1007/s00592-014-0637-4

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  • DOI: https://doi.org/10.1007/s00592-014-0637-4

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