Skip to main content
Book cover

Proteostasis and Disease pp 279–302Cite as

The Role of Proteostasis in the Regulation of Cardiac Intercellular Communication

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1233)

Abstract

Given the low mitotic activity of cardiomyocytes, the contractile unit of the heart, these cells strongly rely on efficient and highly regulated mechanisms of protein degradation to eliminate unwanted potentially toxic proteins. This is particularly important in the context of disease, where an impairment of protein quality control mechanisms underlies the onset and development of diverse cardiovascular maladies. One of the biological processes which is tightly regulated by proteolysis mechanisms is intercellular communication. The different types of cells that form the heart, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, can communicate directly, through gap junctions (GJ) or tunneling nanotubes (TNT), or at long distances, via extracellular vesicles (EV) or soluble factors.

The direct communication between cardiomyocytes is vital to ensure the anisotropic propagation of the electrical impulse, which allows the heart to beat in a coordinated and synchronized manner, as a functional syncytium. The rapid and efficient propagation of the depolarization wave is mainly conducted by low resistance channels called GJ, formed by six subunits of a family of proteins named Cxs. Dysfunctional GJ intercellular communication, due to increased degradation and/or redistribution of connexin43 (Cx43), the main Cx present in the heart, has been associated with several cardiac disorders, such as myocardial ischemia, hypertrophy, arrhythmia, and heart failure. Besides electrical coupling, a fine-tuned exchange of information, namely proteins and microRNAs, conveyed by EV is important to ensure organ function and homeostasis. Disease-induced deregulation of EV-mediated communication between cardiac cells has been implicated in diverse processes such as inflammation, angiogenesis, and fibrosis. Therefore, a better understanding of the mechanisms whereby proteolysis modulates the cross talk between cardiac cells is of utmost importance to develop new strategies to tackle diseases caused by defects in intercellular communication.

Keywords

  • Proteostasis
  • Intercellular communication
  • Cardiovascular diseases
  • Gap junctions
  • Extracellular vesicles
  • Tunneling nanotubes

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-030-38266-7_12
  • Chapter length: 24 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-3-030-38266-7
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   219.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Learn about institutional subscriptions

References

  1. McLendon PM, Robbins J (2015) Proteotoxicity and cardiac dysfunction. Circ Res 116:1863–1882

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  2. Henning RH, Brundel BJJM (2017) Proteostasis in cardiac health and disease. Nat Rev Cardiol 14:637–653

    CAS  CrossRef  PubMed  Google Scholar 

  3. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD, Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD, Mickley H, Crea F, Van de Werf F, Bucciarelli-Ducci C, Katus HA, Pinto FJ, Antman EM, Hamm CW, De Caterina R, Januzzi JL, Apple FS, Alonso Garcia MA, Underwood SR, Canty JM, Lyon AR, Devereaux PJ, Zamorano JL, Lindahl B, Weintraub WS, Newby LK, Virmani R, Vranckx P, Cutlip D, Gibbons RJ, Smith SC, Atar D, Luepker RV, Robertson RM, Bonow RO, Steg PG, O’Gara PT, Fox KAA, Hasdai D, Aboyans V, Achenbach S, Agewall S, Alexander T, Avezum A, Barbato E, Bassand J-P, Bates E, Bittl JA, Breithardt G, Bueno H, Bugiardini R, Cohen MG, Dangas G, de Lemos JA, Delgado V, Filippatos G, Fry E, Granger CB, Halvorsen S, Hlatky MA, Ibanez B, James S, Kastrati A, Leclercq C, Mahaffey KW, Mehta L, Müller C, Patrono C, Piepoli MF, Piñeiro D, Roffi M, Rubboli A, Sharma S, Simpson IA, Tendera M, Valgimigli M, van der Wal AC, Windecker S, Chettibi M, Hayrapetyan H, Roithinger FX, Aliyev F, Sujayeva V, Claeys MJ, Smajić E, Kala P, Iversen KK, El Hefny E, Marandi T, Porela P, Antov S, Gilard M, Blankenberg S, Davlouros P, Gudnason T, Alcalai R, Colivicchi F, Elezi S, Baitova G, Zakke I, Gustiene O, Beissel J, Dingli P, Grosu A, Damman P, Juliebø V, Legutko J, Morais J, Tatu-Chitoiu G, Yakovlev A, Zavatta M, Nedeljkovic M, Radsel P, Sionis A, Jemberg T, Müller C, Abid L, Abaci A, Parkhomenko A, Corbett S (2019) Fourth universal definition of myocardial infarction (2018). Eur Heart J 40:237–269. https://doi.org/10.1093/eurheartj/ehy462

    CrossRef  PubMed  Google Scholar 

  4. Sandri M, Robbins J (2014) Proteotoxicity: an underappreciated pathology in cardiac disease. J Mol Cell Cardiol 71:3–10

    CAS  CrossRef  PubMed  Google Scholar 

  5. Martins-Marques T, Catarino S, Marques C, Pereira P, Girão H (2015a) To beat or not to beat: degradation of Cx43 imposes the heart rhythm. Biochem Soc Trans 43:476–481. https://doi.org/10.1042/bst20150046

    CAS  CrossRef  PubMed  Google Scholar 

  6. Sionis A (2016) Comments on the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 69:1119–1125. https://doi.org/10.1016/j.rec.2016.10.015

    CAS  CrossRef  Google Scholar 

  7. Elliott PM (2015) 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Russ J Cardiol 121:7–57. https://doi.org/10.15829/1560-4071-2015-05-7-57

    CrossRef  Google Scholar 

  8. Fuster V, Rydén LE, Asinger RW (2018) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee. Circulation 104:2118–2150. https://doi.org/10.1161/circ.104.17.2118

    CrossRef  Google Scholar 

  9. Delbridge LMD, Mellor KM, Taylor DJ, Gottlieb RA (2017) Myocardial stress and autophagy: mechanisms and potential therapies. Nat Rev Cardiol 14:412–425

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  10. Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR, Girão H (2017b) Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes. J Cell Sci 130:3619–3630. https://doi.org/10.1242/jcs.200667

    CAS  CrossRef  PubMed  Google Scholar 

  11. Dhein S (1998) Gap junction channels in the cardiovascular system: pharmacological and physiological modulation. Trends Pharmacol Sci 19:229–241. https://doi.org/10.1016/S0165-6147(98)01192-4

    CAS  CrossRef  PubMed  Google Scholar 

  12. Ghafarian F, Pashirzad M, Khazaei M, Hassanian SM, Ferns GA, Avan A (2018) The clinical impact of exosomes in cardiovascular disorders: from basic science to clinical application. J Cell Physiol 234(8):12226–12236. https://doi.org/10.1002/jcp.27964

    CAS  CrossRef  PubMed  Google Scholar 

  13. Severs NJ, Coppen SR, Dupont E, Yeh HI, Ko YS, Matsushita T (2004) Gap junction alterations in human cardiac disease. Cardiovasc Res 62:368–377

    CAS  CrossRef  PubMed  Google Scholar 

  14. Sisakhtnezhad S, Khosravi L (2015) Emerging physiological and pathological implications of tunneling nanotubes formation between cells. Eur J Cell Biol 94:429–443

    CAS  CrossRef  PubMed  Google Scholar 

  15. Dorsch LM, Schuldt M, Knežević D, Wiersma M, Kuster DWD, van der Velden J, Brundel BJJM (2018) Untying the knot: protein quality control in inherited cardiomyopathies. Pflugers Arch Eur J Physiol 471(5):795–806

    CrossRef  Google Scholar 

  16. Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20(7):421–435. https://doi.org/10.1038/s41580-019-0101-y

    CAS  CrossRef  PubMed  Google Scholar 

  17. Schubert U, Antón LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774. https://doi.org/10.1038/35008096

    CAS  CrossRef  PubMed  Google Scholar 

  18. Rujano MA, Bosveld F, Salomons FA, Dijk F, Van Waarde MA, Van Der Want JJ, De Vos RA, Brunt ER, Sibon OC, Kampinga HH (2006) Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol 4:2325–2335. https://doi.org/10.1371/journal.pbio.0040417

    CAS  CrossRef  Google Scholar 

  19. Lau E, Cao Q, Ng DCM, Bleakley BJ, Dincer TU, Bot BM, Wang D, Liem DA, Lam MPY, Ge J, Ping P (2016) A large dataset of protein dynamics in the mammalian heart proteome. Sci Data 3:160015. https://doi.org/10.1038/sdata.2016.15

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  20. Geary B, Magee K, Cash P, Husi H, Young IS, Whitfield PD, Doherty MK (2018) Acute stress alters the rates of degradation of cardiac muscle proteins. J Proteome 191:124–130. https://doi.org/10.1016/j.jprot.2018.03.015

    CAS  CrossRef  Google Scholar 

  21. Golenhofen N, Perng MD, Quinlan RA, Drenckhahn D (2004) Comparison of the small heat shock proteins αb-crystallin, MKBP, HSP25, HSP20, and cvHSP in heart and skeletal muscle. Histochem Cell Biol 122:415–425. https://doi.org/10.1007/s00418-004-0711-z

    CAS  CrossRef  PubMed  Google Scholar 

  22. Kumarapeli ARK, Su H, Huang W, Tang M, Zheng H, Horak KM, Li M, Wang X (2008) αb-crystallin suppresses pressure overload cardiac hypertrophy. Circ Res 103:1473–1482. https://doi.org/10.1161/CIRCRESAHA.108.180117

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  23. Velotta JB, Kimura N, Chang SH, Chung J, Itoh S, Rothbard J, Yang PC, Steinman L, Robbins RC, Fischbein MP (2011) αb-crystallin improves murine cardiac function and attenuates apoptosis in human endothelial cells exposed to ischemia-reperfusion. Ann Thorac Surg 91:1907–1913. https://doi.org/10.1016/j.athoracsur.2011.02.072

    CrossRef  PubMed  Google Scholar 

  24. Arimura T, Ishikawa T, Nunoda S, Kawai S, Kimura A (2011) Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes. Hum Mutat 32:1481–1491. https://doi.org/10.1002/humu.21603

    CAS  CrossRef  PubMed  Google Scholar 

  25. Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S, Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE (2011) Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet 88:273–282. https://doi.org/10.1016/j.ajhg.2011.01.016

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  26. Sanbe A, Marunouchi T, Abe T, Tezuka Y, Okada M, Aoki S, Tsumura H, Yamauchi J, Tanonaka K, Nishigori H, Tanoue A (2013) Phenotype of cardiomyopathy in cardiac-specific heat shock protein B8 K141N transgenic mouse. J Biol Chem 288:8910–8921. https://doi.org/10.1074/jbc.M112.368324

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  27. Schmidt M, Finley D (2014) Regulation of proteasome activity in health and disease. Biochim Biophys Acta, Mol Cell Res 1843:13–25

    CAS  CrossRef  PubMed  Google Scholar 

  28. Tarone G, Brancaccio M (2014) Keep your heart in shape: molecular chaperone networks for treating heart disease. Cardiovasc Res 102:346–361

    CAS  CrossRef  PubMed  Google Scholar 

  29. Martins-Marques T, Ribeiro-Rodrigues T, Pereira P, Codogno P, Girao H (2015c) Autophagy and Ubiquitination in cardiovascular diseases. DNA Cell Biol 34:243–251. https://doi.org/10.1089/dna.2014.2765

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  30. Da Silva-Ferrada E, Ribeiro-Rodrigues TM, Rodríguez MS, Girão H (2016) Proteostasis and SUMO in the heart. Int J Biochem Cell Biol 79:443–450

    CrossRef  PubMed  Google Scholar 

  31. Lokireddy S, Wijesoma IW, Sze SK, McFarlane C, Kambadur R, Sharma M (2012) Identification of atrogin-1-targeted proteins during the myostatin-induced skeletal muscle wasting. Am J Physiol Physiol 303:C512–C529. https://doi.org/10.1152/ajpcell.00402.2011

    CAS  CrossRef  Google Scholar 

  32. Pagan J, Seto T, Pagano M, Cittadini A (2013) Role of the ubiquitin proteasome system in the heart. Circ Res 112:1046–1058

    CAS  CrossRef  PubMed  Google Scholar 

  33. Conraads VM, Vrints CJ, Rodrigus IE, Hoymans VY, Van Craenenbroeck EM, Bosmans J, Claeys MJ, Van Herck P, Linke A, Schuler G, Adams V (2010) Depressed expression of MuRF1 and MAFbx in areas remote of recent myocardial infarction: a mechanism contributing to myocardial remodeling? Basic Res Cardiol 105:219–226. https://doi.org/10.1007/s00395-009-0068-5

    CAS  CrossRef  PubMed  Google Scholar 

  34. Depre C, Wang Q, Yan L, Hedhli N, Peter P, Chen L, Hong C, Hittinger L, Ghaleh B, Sadoshima J, Vatner DE, Vatner SF, Madura K (2006) Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation 114:1821–1828. https://doi.org/10.1161/CIRCULATIONAHA.106.637827

    CAS  CrossRef  PubMed  Google Scholar 

  35. Li HH, Kedar V, Zhang C, McDonough H, Arya R, Wang DZ, Patterson C (2004) Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest 114:1058–1071. https://doi.org/10.1172/jci200422220

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  36. Tang M, Li J, Huang W, Su H, Liang Q, Tian Z, Horak KM, Molkentin JD, Wang X (2010) Proteasome functional insufficiency activates the calcineurin-NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts. Cardiovasc Res 88:424–433. https://doi.org/10.1093/cvr/cvq217

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  37. Chen Q, Liu JB, Horak KM, Zheng H, Kumarapeli ARK, Li J, Li F, Gerdes AM, Wawrousek EF, Wang X (2005) Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res 97:1018–1026. https://doi.org/10.1161/01.RES.0000189262.92896.0b

    CAS  CrossRef  PubMed  Google Scholar 

  38. Zhang X, Qian SB (2011) Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes. Mol Biol Cell 22:3277–3288. https://doi.org/10.1091/mbc.e11-05-0388

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  39. Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C (2009) Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J 28:889–901. https://doi.org/10.1038/emboj.2009.29

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  40. Gurusamy N, Lekli I, Gorbunov NV, Gherghiceanu M, Popescu LM, Das DK (2008) Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein. J Cell Mol Med 13:373–387. https://doi.org/10.1111/j.1582-4934.2008.00495.x

    CrossRef  PubMed  PubMed Central  Google Scholar 

  41. Zhang C (2005) CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice. AJP Hear Circ Physiol 288:H2836–H2842. https://doi.org/10.1152/ajpheart.01122.2004

    CAS  CrossRef  Google Scholar 

  42. Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873

    CAS  CrossRef  PubMed  Google Scholar 

  43. Dikic I, Elazar Z (2018) Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19:349–364

    CAS  CrossRef  PubMed  Google Scholar 

  44. Sánchez-Martín P, Komatsu M (2018) p62/SQSTM1 – steering the cell through health and disease. J Cell Sci 131(21). https://doi.org/10.1242/jcs.222836

  45. 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

    CAS  CrossRef  PubMed  Google Scholar 

  46. Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ (2006) AMP-activated protein kinase and the regulation of Autophagic proteolysis. J Biol Chem 281:34870–34879. https://doi.org/10.1074/jbc.m605488200

    CAS  CrossRef  PubMed  Google Scholar 

  47. Martins-Marques T, Catarino S, Zuzarte M, Marques C, Matafome P, Pereira P, Girão H (2015b) Ischaemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. Biochem J 467:231–245. https://doi.org/10.1042/bj20141370

    CAS  CrossRef  PubMed  Google Scholar 

  48. Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Hill JA, Diwan A (2012) Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation 125:3170–3181. https://doi.org/10.1161/CIRCULATIONAHA.111.041814

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  49. Endo Y, Furuta A, Nishino I (2015) Danon disease: a phenotypic expression of LAMP-2 deficiency. Acta Neuropathol 129:391–398

    CAS  CrossRef  PubMed  Google Scholar 

  50. Ma S, Wang Y, Chen Y, Cao F (2015) The role of the autophagy in myocardial ischemia/reperfusion injury. Biochim Biophys Acta-Mol Basis Dis 1852:271–276

    CAS  CrossRef  Google Scholar 

  51. Saito T, Nah J, Oka SI, Mukai R, Monden Y, Maejima Y, Ikeda Y, Sciarretta S, Liu T, Li H, Baljinnyam E, Fraidenraich D, Fritzky L, Zhai P, Ichinose S, Isobe M, Hsu C-P, Kundu M, Sadoshima J (2018) An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. J Clin Invest 129:802–819. https://doi.org/10.1172/jci122035

    CrossRef  Google Scholar 

  52. Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J (2013) Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 123:5284–5297. https://doi.org/10.1172/JCI70877

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  53. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, Otsu K (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624. https://doi.org/10.1038/nm1574

    CAS  CrossRef  PubMed  Google Scholar 

  54. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793. https://doi.org/10.1172/jci27523

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  55. Yuan Y, Zhao J, Gong Y, Wang D, Wang X, Yun F, Liu Z, Zhang S, Li W, Zhao X, Sun L, Sheng L, Pan Z, Li Y (2018) Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel. Cell Death Dis 9:873. https://doi.org/10.1038/s41419-018-0860-y

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  56. Wiersma M, Meijering RAM, Qi XY, Zhang D, Liu T, Hoogstra-Berends F, Sibon OCM, Henning RH, Nattel S, Brundel BJJM (2017) Endoplasmic reticulum stress is associated with autophagy and cardiomyocyte remodeling in experimental and human atrial fibrillation. J Am Heart Assoc 6. https://doi.org/10.1161/JAHA.117.006458

  57. Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  58. Wing SS, Chiang HL, Goldberg AL, Dice JF (1991) Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J 275(Pt 1):165–169

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  59. Pedrozo Z, Torrealba N, Fernández C, Gatica D, Toro B, Quiroga C, Rodriguez AE, Sanchez G, Gillette TG, Hill JA, Donoso P, Lavandero S (2013) Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. Cardiovasc Res 98:277–285. https://doi.org/10.1093/cvr/cvt029

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  60. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20:143–148. https://doi.org/10.1016/j.cub.2009.11.022

    CAS  CrossRef  PubMed  Google Scholar 

  61. Knezevic T, Myers VD, Gordon J, Tilley DG, Sharp TE, Wang JF, Khalili K, Cheung JY, Feldman AM (2015) BAG3: a new player in the heart failure paradigm. Heart Fail Rev 20:423–434. https://doi.org/10.1007/s10741-015-9487-6

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  62. Patterson C, Portbury AL, Schisler JC, Willis MS (2011) Tear me down: role of calpain in the development of cardiac ventricular hypertrophy. Circ Res 109:453–462. https://doi.org/10.1161/circresaha.110.239749

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  63. Ono Y, Sorimachi H (2012) Calpains – an elaborate proteolytic system. Biochim Biophys Acta 1824:224–236

    CAS  CrossRef  PubMed  Google Scholar 

  64. Inserte J, Hernando V, Garcia-Dorado D (2012) Contribution of calpains to myocardial ischaemia/reperfusion injury. Cardiovasc Res 96:23–31

    CAS  CrossRef  PubMed  Google Scholar 

  65. Galvez AS, Diwan A, Odley AM, Hahn HS, Osinska H, Melendez JG, Robbins J, Lynch RA, Marreez Y, Dorn GW (2007) Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ Res 100:1071–1078. https://doi.org/10.1161/01.res.0000261938.28365.11

    CAS  CrossRef  PubMed  Google Scholar 

  66. Wang Y, Chen B, Huang C-K, Guo A, Wu J, Zhang X, Chen R, Chen C, Kutschke W, Weiss RM, Boudreau RL, Margulies KB, Hong J, Song L-S (2018) Targeting Calpain for heart failure therapy. JACC Basic to Transl Sci 3:503–517. https://doi.org/10.1016/j.jacbts.2018.05.004

    CrossRef  Google Scholar 

  67. Bukowska A, Lendeckel U, Goette A (2014) Atrial calpains: mediators of atrialmyopathies in atrial fibrillation. J Atr Fibrillation 6:104–111

    Google Scholar 

  68. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222. https://doi.org/10.1038/nm1175

    CAS  CrossRef  PubMed  Google Scholar 

  69. Stansfield WE, Tang R-H, Moss NC, Baldwin AS, Willis MS, Selzman CH (2007) Proteasome inhibition promotes regression of left ventricular hypertrophy. Am J Physiol Circ Physiol 294:H645–H650. https://doi.org/10.1152/ajpheart.00196.2007

    CAS  CrossRef  Google Scholar 

  70. McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T, Izumo S (2004) Inhibition of mTOR signaling with Rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055. https://doi.org/10.1161/01.cir.0000130641.08705.45

    CAS  CrossRef  PubMed  Google Scholar 

  71. Zhang CX, Pan SN, Meng RS, Peng CQ, Xiong ZJ, Chen BL, Chen GQ, Yao FJ, Chen YL, Ma YD, Dong YG (2011) Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats. Clin Exp Pharmacol Physiol 38:55–62. https://doi.org/10.1111/j.1440-1681.2010.05461.x

    CAS  CrossRef  PubMed  Google Scholar 

  72. Sanbe A, Daicho T, Mizutani R, Endo T, Miyauchi N, Yamauchi J, Tanonaka K, Glabe C, Tanoue A (2009) Protective effect of Geranylgeranylacetone via enhancement of HSPB8 induction in Desmin-related cardiomyopathy. PLoS One 4:e5351. https://doi.org/10.1371/journal.pone.0005351

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  73. Brundel BJ, Shiroshita-Takeshita A, Qi X, Yeh YH, Chartier D, van Gelder IC, Henning RH, Kampinga HH, Nattel S (2006) Induction of heat shock response protects the heart against atrial fibrillation. Circ Res 99:1394–1402. https://doi.org/10.1161/01.res.0000252323.83137.fe

    CAS  CrossRef  PubMed  Google Scholar 

  74. Kolb PS, Ayaub EA, Zhou W, Yum V, Dickhout JG, Ask K (2015) The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis. Int J Biochem Cell Biol 61:45–52

    CAS  CrossRef  PubMed  Google Scholar 

  75. Sanbe A, Osinska H, Villa C, Gulick J, Klevitsky R, Glabe CG, Kayed R, Robbins J (2005) Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc Natl Acad Sci 102:13592–13597. https://doi.org/10.1073/pnas.0503324102

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  76. Pattison JS, Osinska H, Robbins J (2011) Atg7 induces basal autophagy and rescues autophagic deficiency in CryABR120G cardiomyocytes. Circ Res 109:151–160. https://doi.org/10.1161/CIRCRESAHA.110.237339

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  77. Brundel BJ, Ausma J, van Gelder IC, Van der Want JJ, van Gilst WH, Crijns HJ, Henning RH (2002) Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res 54:380–389

    CAS  CrossRef  PubMed  Google Scholar 

  78. Santo L, Hideshima T, Kung AL, Tseng J-C, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC, Cirstea D, Rodig S, Eda H, Scullen T, Canavese M, Bradner J, Anderson KC, Jones SS, Raje N (2012) Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119:2579–2589. https://doi.org/10.1182/blood-2011-10-387365

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  79. Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J (2003) Progression from compensated hypertrophy to failure in the pressure-overloaded. Circulation 107:984–991. https://doi.org/10.1161/01.CIR.0000051865.66123.B7

    CrossRef  PubMed  Google Scholar 

  80. Lakatta EG (2015) So! What’s aging? Is cardiovascular aging a disease? J Mol Cell Cardiol 83:1–13. https://doi.org/10.1016/j.yjmcc.2015.04.005

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  81. Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA (2014) Microvesicles and exosomes for intracardiac communication. Cardiovasc Res 102:302–311. https://doi.org/10.1093/cvr/cvu022

    CAS  CrossRef  PubMed  Google Scholar 

  82. Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR, Girão H (2017c) Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes. J Cell Sci 130:3619–3630. https://doi.org/10.1242/jcs.200667

    CAS  CrossRef  PubMed  Google Scholar 

  83. Abounit S, Zurzolo C (2012) Wiring through tunneling nanotubes – from electrical signals to organelle transfer. J Cell Sci 125:1089–1098. https://doi.org/10.1242/jcs.083279

    CAS  CrossRef  PubMed  Google Scholar 

  84. Leybaert L, Lampe PD, Dhein S, Kwak BR, Ferdinandy P, Beyer EC, Laird DW, Naus CC, Green CR, Schulz R (2017) Connexins in cardiovascular and neurovascular health and disease: pharmacological implications. Pharmacol Rev 69:396–478. https://doi.org/10.1124/pr.115.012062

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  85. Boulaksil M, Winckels SK, Engelen MA, Stein M, van Veen TA, Jansen JA, Linnenbank AC, Bierhuizen MF, Groenewegen WA, van Oosterhout MF, Kirkels JH, de Jonge N, Varró A, Vos MA, de Bakker JM, van Rijen HV (2010) Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias. Eur J Heart Fail 12:913–921. https://doi.org/10.1093/eurjhf/hfq092

    CAS  CrossRef  PubMed  Google Scholar 

  86. Michela P, Velia V, Aldo P, Ada P (2015) Role of connexin 43 in cardiovascular diseases. Eur J Pharmacol 768:71–76

    CAS  CrossRef  PubMed  Google Scholar 

  87. Dunn CA, Lampe PD (2013) Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J Cell Sci 127:455–464. https://doi.org/10.1242/jcs.142497

    CAS  CrossRef  PubMed  Google Scholar 

  88. Smyth JW, Zhang S-S, Sanchez JM, Lamouille S, Vogan JM, Hesketh GG, Hong T, Tomaselli GF, Shaw RM (2014) A 14-3-3 Mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia. Traffic 15:684–699. https://doi.org/10.1111/tra.12169

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  89. Lindsey ML, Escobar GP, Mukherjee R, Goshorn DK, Sheats NJ, Bruce JA, Mains IM, Hendrick JK, Hewett KW, Gourdie RG, Matrisian LM, Spinale FG (2006) Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113:2919–2928. https://doi.org/10.1161/CIRCULATIONAHA.106.612960

    CAS  CrossRef  PubMed  Google Scholar 

  90. Wu X, Huang W, Luo G, Alain LA (2013) Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling. Mol Cell Biochem 384:155–162. https://doi.org/10.1007/s11010-013-1793-5

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  91. Dupont E, Matsushita T, Kaba RA, Vozzi C, Coppen SR, Khan N, Kaprielian R, Yacoub MH, Severs NJ (2001) Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol 33:359–371. https://doi.org/10.1006/jmcc.2000.1308

    CAS  CrossRef  PubMed  Google Scholar 

  92. Kostin S, Rieger M, Dammer S, Hein S, Richter M, Klövekorn WP, Bauer EP, Schaper J (2003) Gap junction remodeling and altered connexin43 expression in the failing human heart. Mol Cell Biochem 242:135–144. https://doi.org/10.1023/A:1021154115673

    CAS  CrossRef  PubMed  Google Scholar 

  93. Agullo-Pascual E, Lin X, Leo-Macias A, Zhang M, Liang FX, Li Z, Pfenniger A, Lübkemeier I, Keegan S, Fenyo D, Willecke K, Rothenberg E, Delmar M (2014) Super-resolution imaging reveals that loss of the C-terminus of connexin43 limits microtubule plus-end capture and NaV1.5 localization at the intercalated disc. Cardiovasc Res 104:371–381. https://doi.org/10.1093/cvr/cvu195

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  94. Johnson RD, Camelliti P (2018) Role of non-myocyte gap junctions and connexin hemichannels in cardiovascular health and disease: novel therapeutic targets? Int J Mol Sci 19(3). https://doi.org/10.3390/ijms19030866

  95. Ai X, Zhao W, Pogwizd SM (2010) Connexin43 knockdown or overexpression modulates cell coupling in control and failing rabbit left ventricular myocytes. Cardiovasc Res 85:751–762. https://doi.org/10.1093/cvr/cvp353

    CAS  CrossRef  PubMed  Google Scholar 

  96. Glukhov AV, Fedorov VV, Kalish PW, Ravikumar VK, Lou Q, Janks D, Schuessler RB, Moazami N, Efimov IR (2012) Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy. Circulation 125:1835–1847. https://doi.org/10.1161/circulationaha.111.047274

    CrossRef  PubMed  PubMed Central  Google Scholar 

  97. Chen G, Zhao J, Liu C, Zhang Y, Huo Y, Zhou L (2015) MG132 proteasome inhibitor upregulates the expression of connexin 43 in rats with adriamycin-induced heart failure. Mol Med Rep 12:7595–7602. https://doi.org/10.3892/mmr.2015.4337

    CAS  CrossRef  PubMed  Google Scholar 

  98. Givvimani S, Pushpakumar S, Veeranki S, Tyagi SC (2014) Dysregulation of Mfn2 and Drp-1 proteins in heart failure. Can J Physiol Pharmacol 92:583–591. https://doi.org/10.1139/cjpp-2014-0060

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  99. Ovechkin AV, Tyagi N, Rodriguez WE, Hayden MR, Moshal KS, Tyagi SC (2005) Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice. J Appl Physiol 99:2398–2405. https://doi.org/10.1152/japplphysiol.00442.2005

    CAS  CrossRef  PubMed  Google Scholar 

  100. Ribeiro-Rodrigues TM, Catarino S, Pinho MJ, Pereira P, Girao H (2015) Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive. Biochem Soc Trans 43:471–475. https://doi.org/10.1042/bst20150036

    CAS  CrossRef  PubMed  Google Scholar 

  101. Vanslyke JK, Musil LS (2002) Dislocation and degradation from the ER are regulated by cytosolic stress. J Cell Biol 157:381–394. https://doi.org/10.1083/jcb.200111045

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  102. Formigli L, Ibba-Manneschi L, Perna AM, Pacini A, Polidori L, Nediani C, Modesti PA, Nosi D, Tani A, Celli A, Neri-Serneri GG, Quercioli F, Zecchi-Orlandini S (2003) Altered Cx43 expression during myocardial adaptation to acute and chronic volume overloading. Histol Histopathol 18:359–369. https://doi.org/10.14670/HH-18.359

    CAS  CrossRef  PubMed  Google Scholar 

  103. Kostin S, Dammer S, Hein S, Klovekorn WP, Bauer EP, Schaper J (2004) Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc Res 62:426–436. https://doi.org/10.1016/j.cardiores.2003.12.010

    CAS  CrossRef  PubMed  Google Scholar 

  104. Chen H, Yao L, Chen T, Yu M, Wang L, Chen J (2019) Atorvastatin prevents connexin43 remodeling in hypertrophied left ventricular myocardium of spontaneously hypertensive rats. Chin Med J 120:1902–1907. https://doi.org/10.1097/00029330-200711010-00010

    CrossRef  Google Scholar 

  105. Alesutan I, Voelkl J, Stöckigt F, Mia S, Feger M, Primessnig U, Sopjani M, Munoz C, Borst O, Gawaz M, Pieske B, Metzler B, Heinzel F, Schrickel JW, Lang F (2015) AMP-activated protein kinase a1 regulates cardiac gap junction protein connexin 43 and electrical remodeling following pressure overload. Cell Physiol Biochem 35:406–418. https://doi.org/10.1159/000369706

    CAS  CrossRef  PubMed  Google Scholar 

  106. Sun JM, Wang CM, Guo Z, Hao YY, Xie YJ, Gu J, Wang AL (2014a) Reduction of isoproterenol-induced cardiac hypertrophy and modulation of myocardial connexin43 by a KATP channel agonist. Mol Med Rep 11:1845–1850. https://doi.org/10.3892/mmr.2014.2988

    CAS  CrossRef  PubMed  Google Scholar 

  107. Teunissen BE, Jongsma HJ, Bierhuizen MF (2004) Regulation of myocardial connexins during hypertrophic remodelling. Eur Heart J 25:1979–1989

    CAS  CrossRef  PubMed  Google Scholar 

  108. Basheer WA, Harris BS, Mentrup HL, Abreha M, Thames EL, Lea JB, Swing DA, Copeland NG, Jenkins NA, Price RL, Matesic LE (2015) Cardiomyocyte-specific overexpression of the ubiquitin ligase Wwp1 contributes to reduction in Connexin 43 and arrhythmogenesis. J Mol Cell Cardiol 88:1–13. https://doi.org/10.1016/j.yjmcc.2015.09.004

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  109. Kato T, Iwasaki YK, Nattel S (2012) Connexins and atrial fibrillation: filling in the gaps. Circulation 125:203–206

    CrossRef  PubMed  Google Scholar 

  110. Beauchamp P, Yamada KA, Baertschi AJ, Green K, Kanter EM, Saffitz JE, Kléber AG (2006) Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circ Res 99:1216–1224. https://doi.org/10.1161/01.RES.0000250607.34498.b4

    CAS  CrossRef  PubMed  Google Scholar 

  111. Polontchouk L, Haefliger J-A, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, Kuhn-Regnier F, De Vivie ER, Dhein S (2002) Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol 38:883–891. https://doi.org/10.1016/s0735-1097(01)01443-7

    CrossRef  Google Scholar 

  112. Wilhelm M, Kirste W, Kuly S, Amann K, Neuhuber W, Weyand M, Daniel WG, Garlichs C (2006) Atrial distribution of connexin 40 and 43 in patients with intermittent, persistent, and postoperative atrial fibrillation. Hear Lung Circ 15:30–37. https://doi.org/10.1016/j.hlc.2005.06.011

    CAS  CrossRef  Google Scholar 

  113. Gollob MH, Jones DL, Krahn AD, Danis L, Gong X-Q, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D (2006) Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 354:2677–2688. https://doi.org/10.1056/nejmoa052800

    CAS  CrossRef  PubMed  Google Scholar 

  114. Sun Y, Tong X, Chen H, Huang T, Shao Q, Huang W, Laird DW, Bai D (2014b) An atrial-fibrillation-linked connexin40 mutant is retained in the endoplasmic reticulum and impairs the function of atrial gap-junction channels. Dis Model Mech 7:561–569. https://doi.org/10.1242/dmm.013813

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  115. Sinner MF, Tucker NR, Lunetta KL, Ozaki K, Smith JG, Trompet S, Bis JC, Lin H, Chung MK, Nielsen JB, Lubitz SA, Krijthe BP, Magnani JW, Ye J, Gollob MH, Tsunoda T, Müller-Nurasyid M, Lichtner P, Peters A, Dolmatova E, Kubo M, Smith JD, Psaty BM, Smith NL, Jukema JW, Chasman DI, Albert CM, Ebana Y, Furukawa T, Macfarlane PW, Harris TB, Darbar D, Dörr M, Holst AG, Svendsen JH, Hofman A, Uitterlinden AG, Gudnason V, Isobe M, Malik R, Dichgans M, Rosand J, Van Wagoner DR, Benjamin EJ, Milan DJ, Melander O, Heckbert SR, Ford I, Liu Y, Barnard J, Olesen MS, Stricker BHC, Tanaka T, Kääb S, Ellinor PT (2014) Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation 130:1225–1235. https://doi.org/10.1161/CIRCULATIONAHA.114.009892

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  116. Tuomi JM, Tyml K, Jones DL (2011) Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse. Am J Physiol Circ Physiol 300:H1402–H1411. https://doi.org/10.1152/ajpheart.01094.2010

    CAS  CrossRef  Google Scholar 

  117. Mathieu M, Martin-Jaular L, Lavieu G, Théry C (2019) Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21:9–17

    CAS  CrossRef  PubMed  Google Scholar 

  118. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borràs FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan M, Brigstock DR, Brisson A, Broekman MLD, Bromberg JF, Bryl-Górecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzás EI, Byrd JB, Camussi G, Carter DRF, Caruso S, Chamley LW, Chang YT, Chaudhuri AD, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FAW, Coyle B, Crescitelli R, Criado MF, D’Souza-Schorey C, Das S, de Candia P, De Santana EF, De Wever O, del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TAP, Duarte FV, Duncan HM, Eichenberger RM, Ekström K, EL Andaloussi S, Elie-Caille C, Erdbrügger U, Falcón-Pérez JM, Fatima F, Fish JE, Flores-Bellver M, Försönits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gámez-Valero A, Gardiner C, Gärtner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DCI, Görgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AGE, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanović MM, Kovács ÁF, Krämer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lässer C, Laurent LC, Lavieu G, Lázaro-Ibáñez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li ITS, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Linē A, Linnemannstöns K, Llorente A, Lombard CA, Lorenowicz MJ, Lörincz ÁM, Lötvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SLN, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG, Meehan KL, Mertens I, Minciacchi VR, Möller A, Møller Jørgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-’t Hoen ENM, Noren Hooten N, O’Driscoll L, O’Grady T, O’Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostegaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BCH, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IKH, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KMA, Rughetti A, Russell AE, Saá P, Sahoo S, Salas-Huenuleo E, Sánchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schøyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PRM, Silva AM, Skowronek A, Snyder OL, Soares RP, Sódar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BWM, van der Grein SG, Van Deun J, van Herwijnen MJC, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ, Veit TD, Vella LJ, Velot É, Verweij FJ, Vestad B, Viñas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MHM, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yáñez-Mó M, Yin H, Yuana Y, Zappulli V, Zarubova J, Žėkas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7. https://doi.org/10.1080/20013078.2018.1535750

  119. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  120. Soares AR, Martins-Marques T, Ribeiro-Rodrigues T, Ferreira JV, Catarino S, Pinho MJ, Zuzarte M, Isabel Anjo S, Manadas B, Sluijter Joost PG, Pereira P, Girao H (2015) Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci Rep 5:13243. https://doi.org/10.1038/srep13243

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  121. Bei Y, Das S, Rodosthenous RS, Holvoet P, Vanhaverbeke M, Monteiro MC, Monteiro VVS, Radosinska J, Bartekova M, Jansen F, Li Q, Rajasingh J, Xiao J (2017) Extracellular vesicles in cardiovascular theranostics. Theranostics 7:4168–4182. https://doi.org/10.7150/thno.21274

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  122. Jansen F, Nickenig G, Werner N (2017) Extracellular vesicles in cardiovascular disease. Circ Res 120:1649–1657

    CAS  CrossRef  PubMed  Google Scholar 

  123. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, Torre T, Siclari F, Moccetti T, Vassalli G (2014) Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 103:530–541. https://doi.org/10.1093/cvr/cvu167

    CAS  CrossRef  PubMed  Google Scholar 

  124. Gallet R, Dawkins J, Valle J, Simsolo E, De Couto G, Middleton R, Tseliou E, Luthringer D, Kreke M, Smith RR, Marbán L, Ghaleh B, Marbán E (2017) Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J 38:201–211. https://doi.org/10.1093/eurheartj/ehw240

    CAS  CrossRef  PubMed  Google Scholar 

  125. Jiang X, Lew K-S, Chen Q, Richards AM, Wang P (2019) Human mesenchymal stem cell-derived exosomes reduce ischemia/reperfusion injury by the inhibitions of apoptosis and autophagy. Curr Pharm Des 24(44):5334–5341. https://doi.org/10.2174/1381612825666190119130441

    CAS  CrossRef  Google Scholar 

  126. Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, Choo A, Lim SK (2012) Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics 2012:1–14. https://doi.org/10.1155/2012/971907

    CAS  CrossRef  Google Scholar 

  127. Liu H, Gao W, Yuan J, Wu C, Yao K, Zhang L, Ma L, Zhu J, Zou Y, Ge J (2016) Exosomes derived from dendritic cells improve cardiac function via activation of CD4+ T lymphocytes after myocardial infarction. J Mol Cell Cardiol 91:123–133. https://doi.org/10.1016/j.yjmcc.2015.12.028

    CAS  CrossRef  PubMed  Google Scholar 

  128. Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, Zheng Y, Riquelme JA, Kearney J, Sharma V, Multhoff G, Hall AR, Davidson SM (2015) Plasma Exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 65:1525–1536. https://doi.org/10.1016/j.jacc.2015.02.026

    CAS  CrossRef  PubMed  Google Scholar 

  129. Kang K, Ma R, Cai W, Huang W, Paul C, Liang J, Wang Y, Zhao T, Kim HW, Xu M, Millard RW, Wen Z, Wang Y (2015) Exosomes secreted from CXCR4 overexpressing Mesenchymal stem cells promote cardioprotection via Akt signaling pathway following myocardial infarction. Stem Cells Int 2015:659890. https://doi.org/10.1155/2015/659890

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  130. Liu L, Jin X, Hu CF, Li R, Zhou Z, Shen CX (2017) Exosomes derived from Mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways. Cell Physiol Biochem 43:52–68. https://doi.org/10.1159/000480317

    CAS  CrossRef  PubMed  Google Scholar 

  131. Yang Y, Li Y, Chen X, Cheng X, Liao Y, Yu X (2016b) Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. J Mol Med 94:711–724. https://doi.org/10.1007/s00109-016-1387-2

    CAS  CrossRef  PubMed  Google Scholar 

  132. Cambier L, de Couto G, Ibrahim A, Echavez AK, Valle J, Liu W, Kreke M, Smith RR, Marbán L, Marbán E (2017) Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol Med 9:337–352. https://doi.org/10.15252/emmm.201606924

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  133. Almeida Paiva R, Martins-Marques T, Jesus K, Ribeiro-Rodrigues T, Zuzarte M, Silva A, Reis L, da Silva M, Pereira P, Vader P, Petrus Gerardus Sluijter J, Gonçalves L, Cruz MT, Girao H (2019) Ischaemia alters the effects of cardiomyocyte-derived extracellular vesicles on macrophage activation. J Cell Mol Med 23:1137–1151. https://doi.org/10.1111/jcmm.14014

    CAS  CrossRef  PubMed  Google Scholar 

  134. Loyer X, Zlatanova I, Devue C, Yin M, Howangyin KY, Klaihmon P, Guerin CL, Kheloufi M, Vilar J, Zannis K, Fleischmann BK, Hwang DW, Park J, Lee H, Menasché P, Silvestre J-S, Boulanger CM (2018) Intra-cardiac release of extracellular vesicles shapes inflammation following myocardial infarction. Circ Res 123:100–106. https://doi.org/10.1161/circresaha.117.311326

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  135. Feng Y, Huang W, Wani M, Yu X, Ashraf M (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9:e88685. https://doi.org/10.1371/journal.pone.0088685

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  136. Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, Platt MO, Searles CD, Davis ME (2015) Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116:255–263. https://doi.org/10.1161/CIRCRESAHA.116.304360

    CAS  CrossRef  PubMed  Google Scholar 

  137. Santos-Oliveira P, Correia A, Rodrigues T, Ribeiro-Rodrigues TM, Matafome P, Rodríguez-Manzaneque JC, Seiça R, Girão H, Travasso RDM (2015) The force at the tip – modelling tension and proliferation in sprouting angiogenesis. PLoS Comput Biol 11:e1004436. https://doi.org/10.1371/journal.pcbi.1004436

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  138. Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, EL-Andaloussi S, Hwang B, Mulligan MS, Lehtiö J, Nolta JA (2016) Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappab signaling. Stem Cells 34:601–613. https://doi.org/10.1002/stem.2298

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  139. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H (2014) Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med 92:387–397. https://doi.org/10.1007/s00109-013-1110-5

    CAS  CrossRef  PubMed  Google Scholar 

  140. Gonzalez-King H, García NA, Ontoria-Oviedo I, Ciria M, Montero JA, Sepúlveda P (2017) Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells 35:1747–1759. https://doi.org/10.1002/stem.2618

    CAS  CrossRef  PubMed  Google Scholar 

  141. Ibrahim AG, Cheng K, Marbán E (2014) Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports 2:606–619. https://doi.org/10.1016/j.stemcr.2014.04.006

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  142. Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, Mackie AR, Vaughan E, Garikipati VNS, Benedict C, Ramirez V, Lambers E, Ito A, Gao E, Misener S, Luongo T, Elrod J, Qin G, Houser SR, Koch WJ, Kishore R (2015) Embryonic stem cell-derived Exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 117:52–64. https://doi.org/10.1161/CIRCRESAHA.117.305990

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  143. Ribeiro-Rodrigues TM, Laundos TL, Pereira-Carvalho R, Batista-Almeida D, Pereira R, Coelho-Santos V, Silva AP, Fernandes R, Zuzarte M, Enguita FJ, Costa MC, Pinto-do ÓP, Pinto MT, Gouveia P, Ferreira L, Mason JC, Pereira P, Kwak BR, Nascimento DS, Girão H (2017a) Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. Cardiovasc Res 113:1338–1350. https://doi.org/10.1093/cvr/cvx118

    CAS  CrossRef  PubMed  Google Scholar 

  144. Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, Watanabe S, Baba O, Kojima Y, Shizuta S, Imai M, Tamura T, Kita T, Kimura T (2011) Increased MicroRNA-1 and MicroRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet 4:446–454. https://doi.org/10.1161/circgenetics.110.958975

    CAS  CrossRef  PubMed  Google Scholar 

  145. Curcio A, Torella D, Iaconetti C, Pasceri E, Sabatino J, Sorrentino S, Giampà S, Micieli M, Polimeni A, Henning BJ, Leone A, Catalucci D, Ellison GM, Condorelli G, Indolfi C (2013) MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts. PLoS One 8:e70158. https://doi.org/10.1371/journal.pone.0070158

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  146. Terentyev D, Belevych AE, Terentyeva R, Martin MM, Malana GE, Kuhn DE, Abdellatif M, Feldman DS, Elton TS, Györke S (2009) miR-1 overexpression enhances Ca (2+) release and promotes cardiac Arrhythmogenesis by targeting PP2A regulatory hyperphosphorylation of RyR2. Cric Res 104:514–521. https://doi.org/10.1161/CIRCRESAHA.108.181651

    CAS  CrossRef  Google Scholar 

  147. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z (2007) The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 13:486–491. https://doi.org/10.1038/nm1569

    CAS  CrossRef  PubMed  Google Scholar 

  148. Zhang Y, Zhang L, Chu W, Wang B, Zhang J, Zhao M, Li X, Li B, Lu Y, Yang B, Shan H (2010) Tanshinone IIA inhibits miR-1 expression through p38 MAPK signal pathway in post-infarction rat cardiomyocytes. Cell Physiol Biochem 26:991–998. https://doi.org/10.1159/000324012

    CAS  CrossRef  PubMed  Google Scholar 

  149. Zhang Y, Sun L, Zhang Y, Liang H, Li X, Cai R, Wang L, Du W, Zhang R, Li J, Wang Z, Ma N, Wang X, Du Z, Yang B, Gao X, Shan H (2013) Overexpression of microRNA-1 causes atrioventricular block in rodents. Int J Biol Sci 9:445–462. https://doi.org/10.7150/ijbs.4630

    CAS  CrossRef  Google Scholar 

  150. Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, Just A, Remke J, Zimmer K, Zeug A, Ponimaskin E, Schmiedl A, Yin X, Mayr M, Halder R, Fischer A, Engelhardt S, Wei Y, Schober A, Fiedler J, Thum T (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124:2136–2146. https://doi.org/10.1172/JCI70577

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  151. Lyu L, Wang H, Li B, Qin Q, Qi L, Nagarkatti M, Nagarkatti P, Janicki JS, Wang XL, Cui T (2015) A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. J Mol Cell Cardiol 89:268–279. https://doi.org/10.1016/j.yjmcc.2015.10.022

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  152. Fang X, Stroud MJ, Ouyang K, Fang L, Zhang J, Dalton ND, Gu Y, Wu T, Peterson KL, Huang HD, Chen J, Wang N (2016) Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy. JCI Insight 1(16):e89908. https://doi.org/10.1172/jci.insight.89908

    CrossRef  PubMed  PubMed Central  Google Scholar 

  153. Baptista R, Marques C, Catarino S, Enguita FJ, Costa MC, Matafome P, Zuzarte M, Castro G, Reis A, Monteiro P, Pêgo M, Pereira P, Girão H (2017) MicroRNA-424(322) as a new marker of disease progression in pulmonary arterial hypertension and its role in right ventricular hypertrophy by targeting SMURF1. Cardiovasc Res 114:53–64. https://doi.org/10.1093/cvr/cvx187

    CAS  CrossRef  Google Scholar 

  154. Figeac F, Lesault PF, Le Coz O, Damy T, Souktani R, Trébeau C, Schmitt A, Ribot J, Mounier R, Guguin A, Manier C, Surenaud M, Hittinger L, Dubois-Randé JL, Rodriguez AM (2013) Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells. Stem Cells 32:216–230. https://doi.org/10.1002/stem.1560

    CAS  CrossRef  Google Scholar 

  155. Koyanagi M, Brandes RP, Haendeler J, Zeiher AM, Dimmeler S (2005) Cell-to-cell connection of endothelial progenitor cells with cardiac Myocytes by nanotubes: a novel mechanism for cell fate changes? Circ Res 96:1039–1041. https://doi.org/10.1161/01.res.0000168650.23479.0c

    CAS  CrossRef  PubMed  Google Scholar 

  156. Plotnikov EY, Khryapenkova TG, Vasileva AK, Marey MV, Galkina SI, Isaev NK, Sheval EV, Polyakov VY, Sukhikh GT, Zorov DB (2008) Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J Cell Mol Med 12:1622–1631. https://doi.org/10.1111/j.1582-4934.2007.00205.x

    CAS  CrossRef  PubMed  Google Scholar 

  157. Quinn TA, Camelliti P, Rog-Zielinska EA, Siedlecka U, Poggioli T, O’Toole ET, Knöpfel T, Kohl P (2016) Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics. Proc Natl Acad Sci 113:14852–14857. https://doi.org/10.1073/pnas.1611184114

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  158. Shen J, Zhang JH, Xiao H, Wu JM, He KM, Lv ZZ, Li ZJ, Xu M, Zhang YY (2018) Mitochondria are transported along microtubules in membrane nanotubes to rescue distressed cardiomyocytes from apoptosis article. Cell Death Dis 9:81. https://doi.org/10.1038/s41419-017-0145-x

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  159. Yang H, Borg TK, Ma Z, Xu M, Wetzel G, Saraf LV, Markwald R, Runyan RB, Gao BZ (2016a) Biochip-based study of unidirectional mitochondrial transfer from stem cells to myocytes via tunneling nanotubes. Biofabrication 8:015012. https://doi.org/10.1088/1758-5090/8/1/015012

    CAS  CrossRef  PubMed  Google Scholar 

  160. Han H, Hu J, Yan Q, Zhu J, Zhu Z, Chen Y, Sun J, Zhang R (2016) Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep 13:1517–1524. https://doi.org/10.3892/mmr.2015.4726

    CAS  CrossRef  PubMed  Google Scholar 

  161. He K, Shi X, Zhang X, Dang S, Ma X, Liu F, Xu M, Lv Z, Han D, Fang X, Zhang Y (2011) Long-distance intercellular connectivity between cardiomyocytes and cardiofibroblasts mediated by membrane nanotubes. Cardiovasc Res 92:39–47. https://doi.org/10.1093/cvr/cvr189

    CAS  CrossRef  PubMed  Google Scholar 

  162. Herve JC, Sarrouilhe D (2005) Connexin-made channels as pharmacological targets. Curr Pharm Des 11:1941–1958. https://doi.org/10.2174/1381612054021060

    CAS  CrossRef  PubMed  Google Scholar 

  163. García-Dorado D, Rodríguez-Sinovas A, Ruiz-Meana M (2004) Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc Res 61:386–401

    CrossRef  PubMed  Google Scholar 

  164. Dhein S (2004) Pharmacology of gap junctions in the cardiovascular system. Cardiovasc Res 62:287–298. https://doi.org/10.1016/j.cardiores.2004.01.019

    CAS  CrossRef  PubMed  Google Scholar 

  165. Dhein S, Hagen A, Jozwiak J, Dietze A, Garbade J, Barten M, Kostelka M, Mohr FW (2009) Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedeberg's Arch Pharmacol 381:221–234. https://doi.org/10.1007/s00210-009-0473-1

    CAS  CrossRef  Google Scholar 

  166. Colombo M, Raposo G, Théry C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289. https://doi.org/10.1146/annurev-cellbio-101512-122326

    CAS  CrossRef  PubMed  Google Scholar 

  167. Chen GH, Xu J, Yang YJ (2017) Exosomes: promising sacks for treating ischemic heart disease? Am J Physiol Circ Physiol 313:H508–H523. https://doi.org/10.1152/ajpheart.00213.2017

    CrossRef  Google Scholar 

  168. Yellon DM, Davidson SM (2014) Exosomes: nanoparticles involved in cardioprotection? Circ Res 114:325–332. https://doi.org/10.1161/CIRCRESAHA.113.300636

    CAS  CrossRef  PubMed  Google Scholar 

  169. Zhang Y, Hu YW, Zheng L, Wang Q (2017) Characteristics and roles of Exosomes in cardiovascular disease. DNA Cell Biol 36:202–211. https://doi.org/10.1089/dna.2016.3496

    CAS  CrossRef  PubMed  Google Scholar 

  170. Bellin G, Gardin C, Ferroni L, Chachques JC, Rogante M, Mitrečić D, Ferrari R, Zavan B (2019) Exosome in cardiovascular diseases: a complex world full of hope. Cell 8:166. https://doi.org/10.3390/cells8020166

    CAS  CrossRef  Google Scholar 

  171. Cosme J, Liu PP, Gramolini AO (2013) The cardiovascular exosome: current perspectives and potential. Proteomics 13:1654–1659

    CAS  CrossRef  PubMed  Google Scholar 

  172. Pfeifer P, Werner N, Jansen F (2015) Role and function of MicroRNAs in extracellular vesicles in cardiovascular biology. Biomed Res Int 2015:1–11. https://doi.org/10.1155/2015/161393

    CAS  CrossRef  Google Scholar 

  173. Martins-Marques T, Pinho MJ, Zuzarte M, Oliveira C, Pereira P, Sluijter JP, Gomes C, Girao H (2016) Presence of Cx43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin. J Extracell Vesicles 5:32538. https://doi.org/10.3402/jev.v5.32538

    CAS  CrossRef  PubMed  Google Scholar 

  174. Davidson SM, Andreadou I, Barile L, Birnbaum Y, Cabrera-Fuentes HA, Cohen MV, Downey JM, Girao H, Pagliaro P, Penna C, Pernow J, Preissner KT, Ferdinandy P (2018) Circulating blood cells and extracellular vesicles in acute cardioprotection. Cardiovasc Res 115(7):1156–1166. https://doi.org/10.1093/cvr/cvy314

    CAS  CrossRef  PubMed Central  Google Scholar 

  175. Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A, Browman DT, Chenouard N, de Chaumont F, Martino A, Enninga J, Olivo-Marin J-C, Männel D, Zurzolo C (2009) Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol 11:328–336. https://doi.org/10.1038/ncb1841

    CAS  CrossRef  PubMed  Google Scholar 

  176. Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, O’Kane CM, Krasnodembskaya AD (2016) Mitochondrial transfer via tunneling nanotubes is an important mechanism by which Mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells 34:2210–2223. https://doi.org/10.1002/stem.2372

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  177. Sherer NM, Mothes W (2008) Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. Trends Cell Biol 18:414–420

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  178. Mittal R, Karhu E, Wang JS, Delgado S, Zukerman R, Mittal J, Jhaveri VM (2019) Cell communication by tunneling nanotubes: implications in disease and therapeutic applications. J Cell Physiol 234:1130–1146

    CAS  CrossRef  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to all colleagues whose work could not be cited due to space limitations. This work was supported by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE) [under the projects PAC “NETDIAMOND” POCI-01-0145-FEDER-016385, HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323, POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, and FCTUID/NEU/04539/2013 to CNC.IBILI]. DBA was supported by SFRH/BD/115003/2016, TMM by PD/BD/106043/2015, TRR by PD/BD/52294/2013 from Fundação para a Ciência e a Tecnologia (FCT).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), Center for Innovative Biomedicine and Biotechnology (CIBB), Clinical Academic Centre of Coimbra (CACC), University of Coimbra, Coimbra, Portugal

    Daniela Batista-Almeida, Tania Martins-Marques, Teresa Ribeiro-Rodrigues & Henrique Girao

Authors
  1. Daniela Batista-Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tania Martins-Marques
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa Ribeiro-Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henrique Girao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henrique Girao .

Editor information

Editors and Affiliations

  1. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    Rosa Barrio

  2. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    James D. Sutherland

  3. Centre Pierre Potier, ITAV, Toulouse Cedex 1, France

    Manuel S. Rodriguez

Rights and permissions

Reprints and Permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Batista-Almeida, D., Martins-Marques, T., Ribeiro-Rodrigues, T., Girao, H. (2020). The Role of Proteostasis in the Regulation of Cardiac Intercellular Communication. In: Barrio, R., Sutherland, J., Rodriguez, M. (eds) Proteostasis and Disease . Advances in Experimental Medicine and Biology, vol 1233. Springer, Cham. https://doi.org/10.1007/978-3-030-38266-7_12

Download citation