Renal denervation restrains the inflammatory response in myocardial ischemia–reperfusion injury

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Myocardial ischemia–reperfusion (I/R) injury leads to intensive sympathetic nervous system (SNS) activation and inflammatory reactions. Whether renal sympathetic denervation (RDN) could be a new therapeutic strategy to modulate I/R inflammation and reduce infarct size after myocardial I/R injury needs to be explored. First, we investigated the correlation between plasma norepinephrine concentrations and circulating myeloid cell numbers in patients with acute myocardial infarction. And then, C57BL/6 mice underwent a "two-hit" operation, with 10% phenol applied to bilateral renal nerves to abrogate sympathoexcitation, and a 45-min ligation of the left coronary artery to induce myocardial I/R injury. The effects of RDN on the mobilization of immune cells in mice following myocardial I/R injury were explored. We observed a strong association between SNS overactivation and myeloid cell excessive accumulation in patients. In animal experiments, there was a significant reduction in infarct size per area at risk in the denervated-I/R group when compared to that of the innervated-I/R group (39.2% versus 49.8%; p < 0.005), and RDN also improved the left ventricular ejection fraction by 20% after 1 week. Furthermore, the denervated-I/R group showed a decrease in the number of neutrophils and macrophages in the blood and the myocardium as reflected by immunohistochemical staining and flow cytometry analysis (p < 0.05); the decrease was associated with a significant reduction in the circulating production of IL-1, IL-6 and TNF-α (p < 0.05). In summary, our study reveals a novel link between the SNS activity and inflammatory response undergoing myocardium I/R injury and identifies RDN as a potential therapeutic strategy against myocardium I/R injury via preserving the spleen immune cells mobilization.

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  1. 1.

    Baumgart D, Heusch G (1995) Neuronal control of coronary blood flow. Basic Res Cardiol 90:142–159.

  2. 2.

    Binder A, Ali A, Chawla R, Aziz HA, Abbate A, Jovin IS (2015) Myocardial protection from ischemia-reperfusion injury post coronary revascularization. Expert Rev Cardiovasc Ther 13:1045–1057.

  3. 3.

    Bohm M, Ewen S, Mahfoud F (2017) Renal denervation for chronic heart failure: background and pathophysiological rationale. Korean Circ J 47:9–15.

  4. 4.

    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.

  5. 5.

    Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ (2019) Neuroimmune interactions in the gut and their significance for intestinal immunity. Cells.

  6. 6.

    Bucsek MJ, Giridharan T, MacDonald CR, Hylander BL, Repasky EA (2018) An overview of the role of sympathetic regulation of immune responses in infectious disease and autoimmunity. Int J Hyperthermia 34:135–143.

  7. 7.

    Calvillo L, Vanoli E, Andreoli E, Besana A, Omodeo E, Gnecchi M, Zerbi P, Vago G, Busca G, Schwartz PJ (2011) Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc Pharmacol 58:500–507.

  8. 8.

    De Angelis E, Pecoraro M, Rusciano MR, Ciccarelli M, Popolo A (2019) Cross-talk between neurohormonal pathways and the immune system in heart failure: a review of the literature. Int J Mol Sci.

  9. 9.

    Denker MG, Cohen DL (2015) Resistant hypertension and renal nerve denervation. Methodist Debakey Cardiovasc J 11:240–244.

  10. 10.

    Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329.

  11. 11.

    Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638

  12. 12.

    Feng Q, Lu C, Wang L, Song L, Li C, Uppada RC (2017) Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin–angiotensin system in acute myocardial infracted dogs. BMC Cardiovasc Disord 17:65.

  13. 13.

    Fernandez-Ruiz I (2017) Hypertension: proof of concept for renal denervation. Nat Rev Cardiol 14:634.

  14. 14.

    Frangogiannis NG (2015) Inflammation in cardiac injury, repair and regeneration. Curr Opin Cardiol 30:240–245.

  15. 15.

    Fujiu K, Shibata M, Nakayama Y, Ogata F, Matsumoto S, Noshita K, Iwami S, Nakae S, Komuro I, Nagai R, Manabe I (2017) A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation. Nat Med 23:611–622.

  16. 16.

    Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, Fan Q, Chuprun JK, Ma XL, Koch WJ (2010) A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res 107:1445–1453.

  17. 17.

    Gentek R, Hoeffel G (2017) The innate immune response in myocardial infarction, repair, and regeneration. Adv Exp Med Biol 1003:251–272.

  18. 18.

    Hartupee J, Mann DL (2017) Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 14:30–38.

  19. 19.

    Hausenloy DJ, Botker HE, Ferdinandy P, Heusch G, Ng GA, Redington A, Garcia-Dorado D (2019) Cardiac innervation in acute myocardial ischaemia/reperfusion injury and cardioprotection. Cardiovasc Res 115:1167–1177.

  20. 20.

    Heusch G (2008) Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol 153:1589–1601.

  21. 21.

    Heusch G (2019) The spleen in myocardial infarction. Circ Res 124:26–28.

  22. 22.

    Heusch G, Deussen A, Thamer V (1985) Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 13:311–326.

  23. 23.

    Hu J, Yan Y, Zhou Q, Ji M, Niu C, Hou Y, Ge J (2014) Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats. Int J Cardiol 172:e414–416.

  24. 24.

    Kox M, van Eijk LT, Zwaag J, van den Wildenberg J, Sweep FC, van der Hoeven JG, Pickkers P (2014) Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proc Natl Acad Sci U S A 111:7379–7384.

  25. 25.

    Libby P, Nahrendorf M, Swirski FK (2016) Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded "cardiovascular continuum". J Am Coll Cardiol 67:1091–1103.

  26. 26.

    Lieder HR, Kleinbongard P, Skyschally A, Hagelschuer H, Chilian WM, Heusch G (2018) Vago-splenic axis in signal transduction of remote ischemic preconditioning in pigs and rats. Circ Res 123:1152–1163.

  27. 27.

    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.

  28. 28.

    Lubahn CL, Lorton D, Schaller JA, Sweeney SJ, Bellinger DL (2014) Targeting alpha- and beta-adrenergic receptors differentially shifts Th1, Th2, and inflammatory cytokine profiles in immune organs to attenuate adjuvant arthritis. Front Immunol 5:346.

  29. 29.

    Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113:739–753.

  30. 30.

    Mai TH, Wu J, Diedrich A, Garland EM, Robertson D (2014) Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure. J Am Soc Hypertens 8:286–296.

  31. 31.

    Nammas W, Koistinen J, Paana T, Karjalainen PP (2017) Renal sympathetic denervation for treatment of patients with heart failure: summary of the available evidence. Ann Med 49:384–395.

  32. 32.

    Nuntaphum W, Pongkan W, Wongjaikam S, Thummasorn S, Tanajak P, Khamseekaew J, Intachai K, Chattipakorn SC, Chattipakorn N, Shinlapawittayatorn K (2018) Vagus nerve stimulation exerts cardioprotection against myocardial ischemia/reperfusion injury predominantly through its efferent vagal fibers. Basic Res Cardiol 113:22.

  33. 33.

    Oba T, Yasukawa H, Nagata T, Kyogoku S, Minami T, Nishihara M, Ohshima H, Mawatari K, Nohara S, Takahashi J, Sugi Y, Igata S, Iwamoto Y, Kai H, Matsuoka H, Takano M, Aoki H, Fukumoto Y, Imaizumi T (2015) Renal nerve-mediated erythropoietin release confers cardioprotection during remote ischemic preconditioning. Circ J 79(7):1557–1567.

  34. 34.

    Ong SB, Hernandez-Resendiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA, Hausenloy DJ (2018) Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther 186:73–87.

  35. 35.

    Polhemus DJ, Gao J, Scarborough AL, Trivedi R, McDonough KH, Goodchild TT, Smart F, Kapusta DR, Lefer DJ (2016) Radiofrequency renal denervation protects the ischemic heart via inhibition of GRK2 and increased nitric oxide signaling. Circ Res 119:470–480.

  36. 36.

    Polhemus DJ, Trivedi RK, Gao J, Li Z, Scarborough AL, Goodchild TT, Varner KJ, Xia H, Smart FW, Kapusta DR, Lefer DJ (2017) Renal sympathetic denervation protects the failing heart via inhibition of neprilysin activity in the kidney. J Am Coll Cardiol 70:2139–2153.

  37. 37.

    Polhemus DJ, Trivedi RK, Sharp TE, Li Z, Goodchild TT, Scarborough A, de Couto G, Marban E, Lefer DJ (2019) Repeated cell transplantation and adjunct renal denervation in ischemic heart failure: exploring modalities for improving cell therapy efficacy. Basic Res Cardiol 114:9.

  38. 38.

    Reardon C, Murray K, Lomax AE (2018) Neuroimmune communication in health and disease. Physiol Rev 98:2287–2316.

  39. 39.

    Sharp TE 3rd, Polhemus DJ, Li Z, Spaletra P, Jenkins JS, Reilly JP, White CJ, Kapusta DR, Lefer DJ, Goodchild TT (2018) Renal denervation prevents heart failure progression via inhibition of the renin–angiotensin system. J Am Coll Cardiol 72:2609–2621.

  40. 40.

    Shi Y, Li Y, Yin J, Hu H, Xue M, Li X, Cheng W, Wang Y, Li X, Wang Y, Tan J, Yan S (2019) A novel sympathetic neuronal GABAergic signalling system regulates NE release to prevent ventricular arrhythmias after acute myocardial infarction. Acta Physiol (Oxf).

  41. 41.

    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616.

  42. 42.

    Tsioufis C, Papademetriou V, Dimitriadis K, Tsiachris D, Thomopoulos C, Kasiakogias A, Kordalis A, Kefala A, Koutra E, Lau EO, Grassi G, Stefanadis C (2015) Effects of multielectrode renal denervation on cardiac and neurohumoral adaptations in resistant hypertension with cardiac hypertrophy: an EnligHTN I substudy. J Hypertens 33:346–353.

  43. 43.

    Uitterdijk A, Yetgin T, te Lintel HM, Sneep S, Krabbendam-Peters I, van Beusekom HM, Fischer TM, Cornelussen RN, Manintveld OC, Merkus D, Duncker DJ (2015) Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow. Basic Res Cardiol 110:508.

  44. 44.

    Vasamsetti SB, Florentin J, Coppin E, Stiekema LCA, Zheng KH, Nisar MU, Sembrat J, Levinthal DJ, Rojas M, Stroes ESG, Kim K, Dutta P (2018) Sympathetic neuronal activation triggers myeloid progenitor proliferation and differentiation. Immunity 49(93–106):e107.

  45. 45.

    Werner RA, Maya Y, Rischpler C, Javadi MS, Fukushima K, Lapa C, Herrmann K, Higuchi T (2016) Sympathetic nerve damage and restoration after ischemia-reperfusion injury as assessed by (11)C-hydroxyephedrine. Eur J Nucl Med Mol Imaging 43:312–318.

  46. 46.

    Wernli G, Hasan W, Bhattacherjee A, van Rooijen N, Smith PG (2009) Macrophage depletion suppresses sympathetic hyperinnervation following myocardial infarction. Basic Res Cardiol 104:681–693.

  47. 47.

    Winklewski PJ, Radkowski M, Demkow U (2016) Relevance of immune-sympathetic nervous system interplay for the development of hypertension. Adv Exp Med Biol 884:37–43.

  48. 48.

    Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi T, Loperena R, Foss JD, Mernaugh RL, Chen W, Roberts J 2nd, Osborn JW, Itani HA, Harrison DG (2015) Renal denervation prevents immune cell activation and renal inflammation in angiotensin II-induced hypertension. Circ Res 117:547–557.

  49. 49.

    Yin J, Hu H, Li X, Xue M, Cheng W, Wang Y, Xuan Y, Li X, Yang N, Shi Y, Yan S (2016) Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats post-myocardial infarction. Am J Physiol Cell Physiol 310:C41–53.

  50. 50.

    Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A, Ge J (2018) Megakaryocytic leukemia 1 bridges epigenetic activation of NADPH oxidase in macrophages to cardiac ischemia-reperfusion injury. Circulation 138:2820–2836.

  51. 51.

    Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, Gao L, Xie J, Xu B (2019) Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res 115:1205–1216.

  52. 52.

    Zhou M, Liu Y, Xiong L, Quan D, He Y, Tang Y, Huang H, Huang C (2019) Cardiac sympathetic afferent denervation protects against ventricular arrhythmias by modulating cardiac sympathetic nerve activity during acute myocardial infarction. Med Sci Monit 25:1984–1993.

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This work was supported by the Natural Science Foundation of China (Grant numbers 81470371 and 81870358), the Funds for Jiangsu Provincial Key Medical Discipline (ZDXKB2016013), the Key Projects of Science and Technology of Jiangsu Province (BE2019602) and the Programs of the Science Foundation in Nanjing (ZKX17011).

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Correspondence to Jun Xie or Biao Xu.

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Sun, X., Wei, Z., Li, Y. et al. Renal denervation restrains the inflammatory response in myocardial ischemia–reperfusion injury. Basic Res Cardiol 115, 15 (2020).

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  • Renal denervation
  • Sympathetic nervous system activity
  • Myocardial I/R injury
  • Myocardial inflammation