Advertisement

Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia–reperfusion injury

  • Hsing-Hui Su
  • Jiuan-Miaw Liao
  • Yi-Hsin Wang
  • Ke-Min Chen
  • Chia-Wei Lin
  • I-Hui Lee
  • Yi-Ju Li
  • Jing-Yang Huang
  • Shen Kou TsaiEmail author
  • Jiin-Cherng YenEmail author
  • Shiang-Suo HuangEmail author
Original Contribution

Abstract

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia–reperfusion (I–R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I–R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I–R injury and investigate the underlying mechanism in Sprague–Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I–R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-β signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-β signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I–R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I–R injury.

Keywords

Growth differentiation factor 11 Transforming growth factor beta 1 Myocardial ischemia–reperfusion Smad2/3 TGF-β non-canonical pathway 

Notes

Acknowledgements

Cryostat preparation for frozen sections and upright fluorescence microscopy investigations were performed in the Instrument Center of Chung Shan Medical University, which is supported by Chung Shan Medical University and National Science Council, Ministry of Education, Taichung, Taiwan.

Funding

This work was supported by research grants from Taiwan’s Ministry of Science and Technology (MOST) 106-2320-B-040-005 and MOST 106-2314-B-350-003 given to S-SH and S-KT.

Compliance with ethical standards

Conflicts of interest

All authors declare that they have no conflicts of interest.

Supplementary material

395_2019_728_MOESM1_ESM.docx (625 kb)
Supplementary material 1 (DOCX 624 kb)

References

  1. 1.
    Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM (2009) Toll-like receptors in ischemia-reperfusion injury. Shock 32:4–16.  https://doi.org/10.1097/SHK.0b013e318193e333 CrossRefPubMedGoogle Scholar
  2. 2.
    Bolisetty S, Zarjou A, Agarwal A (2017) Heme oxygenase 1 as a therapeutic target in acute kidney injury. Am J Kidney Dis 69:531–545.  https://doi.org/10.1053/j.ajkd.2016.10.037 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Buja LM (2005) Myocardial ischemia and reperfusion injury. Cardiovasc Pathol 14:170–175.  https://doi.org/10.1016/j.carpath.2005.03.006 CrossRefPubMedGoogle Scholar
  5. 5.
    Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83.  https://doi.org/10.1128/MMBR.00031-10 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen KM, Lee HH, Lu KH, Tseng YK, Hsu LS, Chou HL, Lai SC (2004) Association of matrix metalloproteinase-9 and Purkinje cell degeneration in mouse cerebellum caused by Angiostrongylus cantonensis. Int J Parasitol 34:1147–1156.  https://doi.org/10.1016/j.ijpara.2004.07.004 CrossRefPubMedGoogle Scholar
  7. 7.
    Chen LL, Yin H, Huang J (2007) Inhibition of TGF-beta1 signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through angiogenesis and reduction of apoptosis. Cardiovasc Pathol 16:221–230.  https://doi.org/10.1016/j.carpath.2007.02.007 CrossRefPubMedGoogle Scholar
  8. 8.
    Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 15:171–182.  https://doi.org/10.1038/sj.cdd.4402233 CrossRefPubMedGoogle Scholar
  9. 9.
    Chen Y, Rothnie C, Spring D, Verrier E, Venardos K, Kaye D, Phillips DJ, Hedger MP, Smith JA (2014) Regulation and actions of activin A and follistatin in myocardial ischaemia-reperfusion injury. Cytokine 69:255–262.  https://doi.org/10.1016/j.cyto.2014.06.017 CrossRefPubMedGoogle Scholar
  10. 10.
    Choo EH, Lee JH, Park EH, Park HE, Jung NC, Kim TH, Koh YS, Kim E, Seung KB, Park C, Hong KS, Kang K, Song JY, Seo HG, Lim DS, Chang K (2017) Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the regulatory T cell and macrophage polarization. Circulation 135:1444–1457.  https://doi.org/10.1161/CIRCULATIONAHA.116.023106 CrossRefPubMedGoogle Scholar
  11. 11.
    Chow AK, Cena J, Schulz R (2007) Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol 152:189–205.  https://doi.org/10.1038/sj.bjp.0707344 CrossRefPubMedGoogle Scholar
  12. 12.
    Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, Clements-Jewery H, Lambiase PD, Billman GE, Janse MJ, Pugsley MK, Ng GA, Roden DM, Camm AJ, Walker MJ (2013) The Lambeth conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther 139:213–248.  https://doi.org/10.1016/j.pharmthera.2013.04.008 CrossRefPubMedGoogle Scholar
  13. 13.
    Deten A, Holzl A, Leicht M, Barth W, Zimmer HG (2001) Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol 33:1191–1207.  https://doi.org/10.1006/jmcc.2001.1383 CrossRefPubMedGoogle Scholar
  14. 14.
    Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C, Souquere S, Pierron G, Codogno P (2006) NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J Biol Chem 281:30373–30382.  https://doi.org/10.1074/jbc.M602097200 CrossRefPubMedGoogle Scholar
  15. 15.
    Du GQ, Shao ZB, Wu J, Yin WJ, Li SH, Wu J, Weisel RD, Tian JW, Li RK (2017) Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury. Basic Res Cardiol 112:7.  https://doi.org/10.1007/s00395-016-0593-y CrossRefPubMedGoogle Scholar
  16. 16.
    Eltzschig HK, Eckle T (2011) Ischemia and reperfusion–from mechanism to translation. Nat Med 17:1391–1401.  https://doi.org/10.1038/nm.2507 CrossRefPubMedGoogle Scholar
  17. 17.
    Folino A, Losano G, Rastaldo R (2013) Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection. J Cardiovasc Pharmacol 62:567–575.  https://doi.org/10.1097/FJC.0b013e3182a50c45 CrossRefPubMedGoogle Scholar
  18. 18.
    Hariharan N, Zhai P, Sadoshima J (2011) Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal 14:2179–2190.  https://doi.org/10.1089/ars.2010.3488 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Harper SC, Johnson J, Borghetti G, Zhao H, Wang T, Wallner M, Kubo H, Feldsott EA, Yang Y, Joo Y, Gou X, Sabri AK, Gupta P, Myzithras M, Khalil A, Franti M, Houser SR (2018) GDF11 decreases pressure overload-induced hypertrophy, but can cause severe cachexia and premature death. Circ Res 123:1220–1231.  https://doi.org/10.1161/CIRCRESAHA.118.312955 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hashemi M (2014) The study of pentoxifylline drug effects on renal apoptosis and BCL-2 gene expression changes following ischemic reperfusion injury in rat. Iran J Pharm Res 13:181–189PubMedGoogle Scholar
  21. 21.
    Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM, Garcia-Dorado D (2017) Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 38:935–941.  https://doi.org/10.1093/eurheartj/ehw145 CrossRefPubMedGoogle Scholar
  22. 22.
    Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784.  https://doi.org/10.1093/eurheartj/ehw224 CrossRefGoogle Scholar
  23. 23.
    Iles KE, Dickinson DA, Wigley AF, Welty NE, Blank V, Forman HJ (2005) HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells. Free Radic Biol Med 39:355–364.  https://doi.org/10.1016/j.freeradbiomed.2005.03.026 CrossRefPubMedGoogle Scholar
  24. 24.
    Jazwa A, Stoszko M, Tomczyk M, Bukowska-Strakova K, Pichon C, Jozkowicz A, Dulak J (2015) HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses—effects modified by concomitant VEGF overexpression. Vascul Pharmacol 71:127–138.  https://doi.org/10.1016/j.vph.2015.02.011 CrossRefPubMedGoogle Scholar
  25. 25.
    Jensen EC (2013) Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec (Hoboken) 296:378–381.  https://doi.org/10.1002/ar.22641 CrossRefGoogle Scholar
  26. 26.
    Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317.  https://doi.org/10.1016/b978-0-12-394309-5.00006-7 CrossRefPubMedGoogle Scholar
  27. 27.
    Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714.  https://doi.org/10.1016/j.redox.2014.05.006 CrossRefPubMedGoogle Scholar
  28. 28.
    Khalil AM, Dotimas H, Kahn J, Lamerdin JE, Hayes DB, Gupta P, Franti M (2016) Differential binding activity of TGF-beta family proteins to select TGF-beta receptors. J Pharmacol Exp Ther 358:423–430.  https://doi.org/10.1124/jpet.116.232322 CrossRefPubMedGoogle Scholar
  29. 29.
    Li Q, Guo Y, Tan W, Stein AB, Dawn B, Wu WJ, Zhu X, Lu X, Xu X, Siddiqui T, Tiwari S, Bolli R (2006) Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences. Am J Physiol Heart Circ Physiol 290:H584–H589.  https://doi.org/10.1152/ajpheart.00855.2005 CrossRefPubMedGoogle Scholar
  30. 30.
    Li S, Nie EH, Yin Y, Benowitz LI, Tung S, Vinters HV, Bahjat FR, Stenzel-Poore MP, Kawaguchi R, Coppola G, Carmichael ST (2015) GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat Neurosci 18:1737–1745.  https://doi.org/10.1038/nn.4146 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838.  https://doi.org/10.1152/ajpheart.00335.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall’Osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, Lee RT (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–839.  https://doi.org/10.1016/j.cell.2013.04.015 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ma S, Wang Y, Chen Y, Cao F (2015) The role of the autophagy in myocardial ischemia/reperfusion injury. Biochim Biophys Acta 1852:271–276.  https://doi.org/10.1016/j.bbadis.2014.05.010 CrossRefPubMedGoogle Scholar
  34. 34.
    Marinkovic D, Zhang X, Yalcin S, Luciano JP, Brugnara C, Huber T, Ghaffari S (2007) Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 117:2133–2144.  https://doi.org/10.1172/jci31807 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922.  https://doi.org/10.1161/01.RES.0000261924.76669.36 CrossRefPubMedGoogle Scholar
  36. 36.
    Miyazono K (2000) Positive and negative regulation of TGF-beta signaling. J Cell Sci 113(Pt 7):1101–1109PubMedGoogle Scholar
  37. 37.
    Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, Campo G, Pinton P (2015) Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury. J Mol Cell Cardiol 78:142–153.  https://doi.org/10.1016/j.yjmcc.2014.08.015 CrossRefPubMedGoogle Scholar
  38. 38.
    Mozaffari MS, Liu JY, Abebe W, Baban B (2013) Mechanisms of load dependency of myocardial ischemia reperfusion injury. Am J Cardiovasc Dis 3:180–196PubMedPubMedCentralGoogle Scholar
  39. 39.
    Opstad TB, Seljeflot I, Bohmer E, Arnesen H, Halvorsen S (2017) MMP-9 and its regulators TIMP-1 and EMMPRIN in patients with acute ST-elevation myocardial infarction: a NORDISTEMI substudy. Cardiology 139:17–24.  https://doi.org/10.1159/000481684 CrossRefPubMedGoogle Scholar
  40. 40.
    Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M (2015) Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol 4:184–192.  https://doi.org/10.1016/j.redox.2014.12.003 CrossRefPubMedGoogle Scholar
  41. 41.
    Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348.  https://doi.org/10.1126/science.1193497 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rochette L, Zeller M, Cottin Y, Vergely C (2015) Growth and differentiation factor 11 (GDF11): functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther 156:26–33.  https://doi.org/10.1016/j.pharmthera.2015.10.006 CrossRefPubMedGoogle Scholar
  43. 43.
    Saito T, Rodger IW, Shennib H, Hu F, Tayara L, Giaid A (2003) Cyclooxygenase-2 (COX-2) in acute myocardial infarction: cellular expression and use of selective COX-2 inhibitor. Can J Physiol Pharmacol 81:114–119.  https://doi.org/10.1139/y03-023 CrossRefPubMedGoogle Scholar
  44. 44.
    Schofield ZV, Woodruff TM, Halai R, Wu MC, Cooper MA (2013) Neutrophils—a key component of ischemia-reperfusion injury. Shock 40:463–470.  https://doi.org/10.1097/shk.0000000000000044 CrossRefPubMedGoogle Scholar
  45. 45.
    Su HH, Chu YC, Liao JM, Wang YH, Jan MS, Lin CW, Wu CY, Tseng CY, Yen JC, Huang SS (2017) Phellinus linteus mycelium alleviates myocardial ischemia-reperfusion injury through autophagic regulation. Front Pharmacol 8:175.  https://doi.org/10.3389/fphar.2017.00175 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Traylor A, Hock T, Hill-Kapturczak N (2007) Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-beta1 in renal epithelial cells. Am J Physiol Renal Physiol 293:F885–F894.  https://doi.org/10.1152/ajprenal.00519.2006 CrossRefPubMedGoogle Scholar
  47. 47.
    Walker RG, Poggioli T, Katsimpardi L, Buchanan SM, Oh J, Wattrus S, Heidecker B, Fong YW, Rubin LL, Ganz P, Thompson TB, Wagers AJ, Lee RT (2016) Biochemistry and biology of GDF11 and myostatin: similarities, differences, and questions for future investigation. Circ Res 118:1125–1141.  https://doi.org/10.1161/circresaha.116.308391 (discussion 1142) CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang J, Hu X, Jiang H (2015) The Nrf-2/ARE-HO-1 axis: an important therapeutic approach for attenuating myocardial ischemia and reperfusion injury-induced cardiac remodeling. Int J Cardiol 184:263–264.  https://doi.org/10.1016/j.ijcard.2015.02.073 CrossRefPubMedGoogle Scholar
  49. 49.
    Wang YH, Chen KM, Chiu PS, Lai SC, Su HH, Jan MS, Lin CW, Lu DY, Fu YT, Liao JM, Chang JT, Huang SS (2016) Lumbrokinase attenuates myocardial ischemia-reperfusion injury by inhibiting TLR4 signaling. J Mol Cell Cardiol 99:113–122.  https://doi.org/10.1016/j.yjmcc.2016.08.004 CrossRefPubMedGoogle Scholar
  50. 50.
    Whelan RS, Kaplinskiy V, Kitsis RN (2010) Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol 72:19–44.  https://doi.org/10.1146/annurev.physiol.010908.163111 CrossRefPubMedGoogle Scholar
  51. 51.
    WHO (2018) The top 10 causes of death. In: Media Centre World Health Organization. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
  52. 52.
    Yang Y, Yang Y, Wang X, Du J, Hou J, Feng J, Tian Y, He L, Li X, Pei H (2017) Does growth differentiation factor 11 protect against myocardial ischaemia/reperfusion injury? A hypothesis. J Int Med Res 45:1629–1635.  https://doi.org/10.1177/0300060516658984 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department and Institute of Pharmacology, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Department of PhysiologyChung Shan Medical University and Chung Shan Medical University HospitalTaichungTaiwan
  3. 3.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  4. 4.Department of ParasitologyChung Shan Medical UniversityTaichungTaiwan
  5. 5.Institute of Biochemistry, Microbiology and ImmunologyMedical College of Chung Shan Medical UniversityTaichungTaiwan
  6. 6.Department of NeurologyTaipei Veterans General HospitalTaipeiTaiwan
  7. 7.Institute of Brain ScienceNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.Department of PathologyChung Shan Medical UniversityTaichungTaiwan
  9. 9.Department of PathologyChung Shan Medical University HospitalTaichungTaiwan
  10. 10.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
  11. 11.Cheng-Hsin General HospitalTaipeiTaiwan
  12. 12.Department of PharmacologyChung Shan Medical UniversityTaichungTaiwan
  13. 13.Department of PharmacyChung Shan Medical University HospitalTaichungTaiwan

Personalised recommendations