Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Molecular Signatures of Sinus Node Dysfunction Induce Structural Remodeling in the Right Atrial Tissue

  • Roh, Seung-Young (Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Guro Hospital) ;
  • Kim, Ji Yeon (Department of Biomedical Sciences, College of Medicine, Korea University) ;
  • Cha, Hyo Kyeong (Department of Biomedical Sciences, College of Medicine, Korea University) ;
  • Lim, Hye Young (Department of Biomedical Sciences, College of Medicine, Korea University) ;
  • Park, Youngran (Department of Biomedical Sciences, College of Medicine, Korea University) ;
  • Lee, Kwang-No (Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Anam Hospital) ;
  • Shim, Jaemin (Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Anam Hospital) ;
  • Choi, Jong-Il (Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Anam Hospital) ;
  • Kim, Young-Hoon (Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine and Korea University Anam Hospital) ;
  • Son, Gi Hoon (Department of Biomedical Sciences, College of Medicine, Korea University)
  • Received : 2019.07.22
  • Accepted : 2020.03.05
  • Published : 2020.04.30
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Abstract

The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (SND)-characterized by electrical remodeling-is generally attributed to idiopathic fibrosis or ischemic injuries in the SN. SND is associated with increased risk of cardiovascular disorders, including syncope, heart failure, and atrial arrhythmias, particularly atrial fibrillation. One of the histological SND hallmarks is degenerative atrial remodeling that is associated with conduction abnormalities and increased right atrial refractoriness. Although SND is frequently accompanied by increased fibrosis in the right atrium (RA), its molecular basis still remains elusive. Therefore, we investigated whether SND can induce significant molecular changes that account for the structural remodeling of RA. Towards this, we employed a rabbit model of experimental SND, and then compared the genome-wide RNA expression profiles in RA between SND-induced rabbits and sham-operated controls to identify the differentially expressed transcripts. The accompanying gene enrichment analysis revealed extensive pro-fibrotic changes within 7 days after the SN ablation, including activation of transforming growth factor-β (TGF-β) signaling and alterations in the levels of extracellular matrix components and their regulators. Importantly, our findings suggest that periostin, a matricellular factor that regulates the development of cardiac tissue, might play a key role in mediating TGF-β-signaling-induced aberrant atrial remodeling. In conclusion, the present study provides valuable information regarding the molecular signatures underlying SND-induced atrial remodeling, and indicates that periostin can be potentially used in the diagnosis of fibroproliferative cardiac dysfunctions.

Keywords

References

  1. Abe, K., Machida, T., Sumitomo, N., Yamamoto, H., Ohkubo, K., Watanabe, I., Makiyama, T., Fukae, S., Kohno, M., Harrell, D.T., et al. (2014). Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ. Arrhythm. Electrophysiol. 7, 511-517. https://doi.org/10.1161/CIRCEP.113.001340
  2. Alonso, A., Jensen, P.N., Lopez, F.L., Chen, L.Y., Psaty, B.M., Folsom, A.R., and Heckbert, S.R. (2014). Association of sick sinus syndrome with incident cardiovascular disease and mortality: the atherosclerosis risk in communities study and cardiovascular health study. PLoS One 9, e109662. https://doi.org/10.1371/journal.pone.0109662
  3. Amasyali, B., Kilic, A., and Kilit, C. (2014). Sinus node dysfunction and atrial fibrillation: which one dominates? Int. J. Cardiol. 175, 379-380. https://doi.org/10.1016/j.ijcard.2014.05.043
  4. Andersen, H.R., Nielsen, J.C., Thomsen, P.E., Thuesen, L., Mortensen, P.T., Vesterlund, T., and Pedersen, A.K. (1997). Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 350, 1210-1216. https://doi.org/10.1016/S0140-6736(97)03425-9
  5. Assayag, P., Carre, F., Chevalier, B., Delcayre, C., Mansier, P., and Swynghedauw, B. (1997). Compensated cardiac hypertrophy: arrhythmogenicity and the new myocardial phenotype. I. fibrosis. Cardiovasc. Res. 34, 439-444. https://doi.org/10.1016/S0008-6363(97)00073-4
  6. Bernstein, A.D. and Parsonnet, V. (1996). Survey of cardiac pacing and defibrillation in the United States in 1993. Am. J. Cardiol. 78, 187-196. https://doi.org/10.1016/S0002-9149(96)00255-X
  7. Bujor, A.M., Asano, Y., Haines, P., Lafyatis, R., and Trojanowska, M. (2011). The c-Abl tyrosine kinase controls protein kinase Cdelta-induced Fli-1 phosphorylation in human dermal fibroblasts. Arthritis Rheum. 63, 1729-1737.
  8. Chung, S., Kim, I.H., Lee, D., Park, K., Kim, J.Y., Lee, Y.K., Kim, E.J., Lee, H.W., Choi, J.S., Son, G.H., et al. (2016). The role of inositol 1,4,5-trisphosphate 3-kinase A in regulating emotional behavior and amygdala function. Sci. Rep. 6, 23757. https://doi.org/10.1038/srep23757
  9. Chung, S., Lee, E.J., Cha, H.K., Kim, J., Kim, D., Son, G.H., and Kim, K. (2017). Cooperative roles of the suprachiasmatic nucleus central clock and the adrenal clock in controlling circadian glucocorticoid rhythm. Sci. Rep. 7, 46404. https://doi.org/10.1038/srep46404
  10. Connolly, S.J., Kerr, C.R., Gent, M., Roberts, R.S., Yusuf, S., Gillis, A.M., Sami, M.H., Talajic, M., Tang, A.S., Klein, G.J., et al. (2000). Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian trial of physiologic pacing investigators. N. Engl. J. Med. 342, 1385-1391. https://doi.org/10.1056/NEJM200005113421902
  11. Dobrzynski, H., Boyett, M.R., and Anderson, R.H. (2007). New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 115, 1921-1932. https://doi.org/10.1161/CIRCULATIONAHA.106.616011
  12. Ellmers, L.J., Scott, N.J., Piuhola, J., Maeda, N., Smithies, O., Frampton, C.M., Richards, A.M., and Cameron, V.A. (2007). Npr1-regulated gene pathways contributing to cardiac hypertrophy and fibrosis. J. Mol. Endocrinol. 38, 245. https://doi.org/10.1677/jme.1.02138
  13. Ge, J., Burnier, L., Adamopoulou, M., Kwa, M.Q., Schaks, M., Rottner, K., and Brakebusch, C. (2018). RhoA, Rac1, and Cdc42 differentially regulate alphaSMA and collagen I expression in mesenchymal stem cells. J. Biol. Chem. 293, 9358-9369. https://doi.org/10.1074/jbc.RA117.001113
  14. He, X., Zhang, K., Gao, X., Li, L., Tan, H., Chen, J., and Zhou, Y. (2016). Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit. Heart Vessels 31, 1696-1708. https://doi.org/10.1007/s00380-016-0808-z
  15. Herrmann, S., Fabritz, L., Layh, B., Kirchhof, P., and Ludwig, A. (2011). Insights into sick sinus syndrome from an inducible mouse model. Cardiovasc. Res. 90, 38-48. https://doi.org/10.1093/cvr/cvq390
  16. Iekushi, K., Taniyama, Y., Azuma, J., Katsuragi, N., Dosaka, N., Sanada, F., Koibuchi, N., Nagao, K., Ogihara, T., and Morishita, R. (2007). Novel mechanisms of valsartan on the treatment of acute myocardial infarction through inhibition of the antiadhesion molecule periostin. Hypertension 49, 1409-1414. https://doi.org/10.1161/HYPERTENSIONAHA.106.080994
  17. Inoue, T., Akashi, K., Watanabe, M., Ikeda, Y., Ashizuka, S., Motoki, T., Suzuki, R., Sagara, N., Yanagida, N., Sato, S., et al. (2016). Periostin as a biomarker for the diagnosis of pediatric asthma. Pediatr. Allergy Immunol. 27, 521-526. https://doi.org/10.1111/pai.12575
  18. Jensen, P.N., Gronroos, N.N., Chen, L.Y., Folsom, A.R., deFilippi, C., Heckbert, S.R., and Alonso, A. (2014). Incidence of and risk factors for sick sinus syndrome in the general population. J. Am. Coll. Cardiol. 64, 531-538. https://doi.org/10.1016/j.jacc.2014.03.056
  19. John, R.M. and Kumar, S. (2016). Sinus node and atrial arrhythmias. Circulation 133, 1892-1900. https://doi.org/10.1161/CIRCULATIONAHA.116.018011
  20. Joung, B., Lin, S.F., Chen, Z., Antoun, P.S., Maruyama, M., Han, S., Piccirillo, G., Stucky, M., Zipes, D.P., Chen, P.S., et al. (2010). Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm 7, 88-95. https://doi.org/10.1016/j.hrthm.2009.09.018
  21. Kii, I., Nishiyama, T., Li, M., Matsumoto, K., Saito, M., Amizuka, N., and Kudo, A. (2010). Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J. Biol. Chem. 285, 2028-2039. https://doi.org/10.1074/jbc.M109.051961
  22. Kim, J.Y., Lim, H.Y., Shin, S.E., Cha, H.K., Seo, J.H., Kim, S.K., Park, S.H., and Son, G.H. (2018). Comprehensive transcriptome analysis of Sarcophaga peregrina, a forensically important fly species. Sci. Data 5, 180220. https://doi.org/10.1038/sdata.2018.220
  23. Lamas, G.A., Lee, K.L., Sweeney, M.O., Silverman, R., Leon, A., Yee, R., Marinchak, R.A., Flaker, G., Schron, E., Orav, E.J., et al. (2002). Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N. Engl. J. Med. 346, 1854-1862. https://doi.org/10.1056/NEJMoa013040
  24. Landry, N.M., Cohen, S., and Dixon, I.M.C. (2018). Periostin in cardiovascular disease and development: a tale of two distinct roles. Basic Res. Cardiol. 113, 1. https://doi.org/10.1007/s00395-017-0659-5
  25. Li, G., Jin, R., Norris, R.A., Zhang, L., Yu, S., Wu, F., Markwald, R.R., Nanda, A., Conway, S.J., Smyth, S.S., et al. (2010). Periostin mediates vascular smooth muscle cell migration through the integrins alphavbeta3 and alphavbeta5 and focal adhesion kinase (FAK) pathway. Atherosclerosis 208, 358-365. https://doi.org/10.1016/j.atherosclerosis.2009.07.046
  26. Li, G., Liu, E., Liu, T., Wang, J., Dai, J., Xu, G., Korantzopoulos, P., and Yang, W. (2011). Atrial electrical remodeling in a canine model of sinus node dysfunction. Int. J. Cardiol. 146, 32-36. https://doi.org/10.1016/j.ijcard.2009.06.002
  27. Li, P., Oparil, S., Novak, L., Cao, X., Shi, W., Lucas, J., and Chen, Y.F. (2007). ANP signaling inhibits TGF-beta-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells. J. Appl. Physiol. 102, 390-398. https://doi.org/10.1152/japplphysiol.00468.2006
  28. Lindner, V., Wang, Q., Conley, B.A., Friesel, R.E., and Vary, C.P. (2005). Vascular injury induces expression of periostin: implications for vascular cell differentiation and migration. Arterioscler. Thromb. Vasc. Biol. 25, 77-83. https://doi.org/10.1161/01.ATV.0000149141.81230.c6
  29. Liu, R.X., Wang, Y.L., Li, H.B., Wang, N.N., Bao, M.J., and Xu, L.Y. (2012). Comparative study between original and traditional method in establishing a chronic sinus node damage model in rabbit. J. Appl. Physiol. 113, 1802-1808. https://doi.org/10.1152/japplphysiol.00480.2012
  30. Markwald, R.R., Norris, R.A., Moreno-Rodriguez, R., and Levine, R.A. (2010). Developmental basis of adult cardiovascular diseases: valvular heart diseases. Ann. N. Y. Acad. Sci. 1188, 177-183. https://doi.org/10.1111/j.1749-6632.2009.05098.x
  31. Maruhashi, T., Kii, I., Saito, M., and Kudo, A. (2010). Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase. J. Biol. Chem. 285, 13294-13303. https://doi.org/10.1074/jbc.M109.088864
  32. Medi, C., Kalman, J.M., Ling, L.H., Teh, A.W., Lee, G., Lee, G., Spence, S.J., Kaye, D.M., and Kistler, P.M. (2012). Atrial electrical and structural remodeling associated with longstanding pulmonary hypertension and right ventricular hypertrophy in humans. J. Cardiovasc. Electrophysiol. 23, 614-620. https://doi.org/10.1111/j.1540-8167.2011.02255.x
  33. Morillo, C.A., Klein, G.J., Jones, D.L., and Guiraudon, C.M. (1995). Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 91, 1588-1595. https://doi.org/10.1161/01.CIR.91.5.1588
  34. Morton, J.B., Sanders, P., Vohra, J.K., Sparks, P.B., Morgan, J.G., Spence, S.J., Grigg, L.E., and Kalman, J.M. (2003). Effect of chronic right atrial stretch on atrial electrical remodeling in patients with an atrial septal defect. Circulation 107, 1775-1782. https://doi.org/10.1161/01.CIR.0000058164.68127.F2
  35. Mu, Y., Gudey, S.K., and Landstrom, M. (2012). Non-Smad signaling pathways. Cell Tissue Res. 347, 11-20. https://doi.org/10.1007/s00441-011-1201-y
  36. Mulla, W., Hajaj, B., Elyagon, S., Mor, M., Gillis, R., Murninkas, M., Klapper- Goldstein, H., Plaschkes, I., Chalifa-Caspi, V., Etzion, S., et al. (2019). Rapid atrial pacing promotes atrial fibrillation substrate in unanesthetized instrumented rats. Front. Physiol. 10, 1218. https://doi.org/10.3389/fphys.2019.01218
  37. Nielsen, J.C., Thomsen, P.E., Hojberg, S., Moller, M., Vesterlund, T., Dalsgaard, D., Mortensen, L.S., Nielsen, T., Asklund, M., Friis, E.V., et al. (2011). A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. Eur. Heart J. 32, 686-696. https://doi.org/10.1093/eurheartj/ehr022
  38. Norris, R.A., Damon, B., Mironov, V., Kasyanov, V., Ramamurthi, A., Moreno-Rodriguez, R., Trusk, T., Potts, J.D., Goodwin, R.L., Davis, J., et al. (2007). Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J. Cell. Biochem. 101, 695-711. https://doi.org/10.1002/jcb.21224
  39. Oka, T., Xu, J., Kaiser, R.A., Melendez, J., Hambleton, M., Sargent, M.A., Lorts, A., Brunskill, E.W., Dorn, G.W., 2nd, Conway, S.J., et al. (2007). Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ. Res. 101, 313-321. https://doi.org/10.1161/CIRCRESAHA.107.149047
  40. Pinto, A.R., Ilinykh, A., Ivey, M.J., Kuwabara, J.T., D'Antoni, M.L., Debuque, R., Chandran, A., Wang, L., Arora, K., Rosenthal, N.A., et al. (2016). Revisiting cardiac cellular composition. Circ. Res. 118, 400-409. https://doi.org/10.1161/CIRCRESAHA.115.307778
  41. Platonov, P.G. (2017). Atrial fibrosis: an obligatory component of arrhythmia mechanisms in atrial fibrillation? J. Geriatr. Cardiol. 14, 233-237.
  42. Prakoura, N. and Chatziantoniou, C. (2017). Periostin and discoidin domain receptor 1: new biomarkers or targets for therapy of renal disease. Front. Med. (Lausanne) 4, 52. https://doi.org/10.3389/fmed.2017.00052
  43. Rahmutula, D., Zhang, H., Wilson, E.E., and Olgin, J.E. (2019). Absence of natriuretic peptide clearance receptor attenuates TGF-${\beta}1$-induced selective atrial fibrosis and atrial fibrillation. Cardiovasc. Res. 115, 357. https://doi.org/10.1093/cvr/cvy224
  44. Rosenkranz, S. (2004). TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc. Res. 63, 423-432. https://doi.org/10.1016/j.cardiores.2004.04.030
  45. Sanders, P., Morton, J.B., Kistler, P.M., Spence, S.J., Davidson, N.C., Hussin, A., Vohra, J.K., Sparks, P.B., and Kalman, J.M. (2004). Electrophysiological and electroanatomic characterization of the atria in sinus node disease: evidence of diffuse atrial remodeling. Circulation 109, 1514-1522. https://doi.org/10.1161/01.CIR.0000121734.47409.AA
  46. Shi, Y. and Massague, J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685-700. https://doi.org/10.1016/S0092-8674(03)00432-X
  47. Shimazaki, M., Nakamura, K., Kii, I., Kashima, T., Amizuka, N., Li, M., Saito, M., Fukuda, K., Nishiyama, T., Kitajima, S., et al. (2008). Periostin is essential for cardiac healing after acute myocardial infarction. J. Exp. Med. 205, 295-303. https://doi.org/10.1084/jem.20071297
  48. Shinde, A.V., Humeres, C., and Frangogiannis, N.G. (2017). The role of alpha-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 298-309. https://doi.org/10.1016/j.bbadis.2016.11.006
  49. Silver, M.A., Pick, R., Brilla, C.G., Jalil, J.E., Janicki, J.S., and Weber, K.T. (1990). Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis. Cardiovasc. Res. 24, 741-747. https://doi.org/10.1093/cvr/24.9.741
  50. Snider, P., Hinton, R.B., Moreno-Rodriguez, R.A., Wang, J., Rogers, R., Lindsley, A., Li, F., Ingram, D.A., Menick, D., Field, L., et al. (2008). Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ. Res. 102, 752-760. https://doi.org/10.1161/CIRCRESAHA.107.159517
  51. Taniyama, Y., Katsuragi, N., Sanada, F., Azuma, J., Iekushi, K., Koibuchi, N., Okayama, K., Ikeda-Iwabu, Y., Muratsu, J., Otsu, R., et al. (2016). Selective blockade of periostin exon 17 preserves caediac performance in acute myocardial infarction. Hypertension 67, 356-361. https://doi.org/10.1161/HYPERTENSIONAHA.115.06265
  52. Thanigaimani, S., Lau, D.H., Agbaedeng, T., Elliott, A.D., Mahajan, R., and Sanders, P. (2017). Molecular mechanisms of atrial fibrosis: implications for the clinic. Expert Rev. Cardiovasc. Ther. 15, 247-256. https://doi.org/10.1080/14779072.2017.1299005
  53. Wang, D., Oparil, S., Feng, J.A., Li, P., Perry, G., Chen, L.B., Dai, M., John, S.W., and Chen, Y.F. (2003). Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 42, 88-95. https://doi.org/10.1161/01.HYP.0000074905.22908.A6
  54. Weber, K.T., Sun, Y., Bhattacharya, S.K., Ahokas, R.A., and Gerling, I.C. (2013). Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat. Rev. Cardiol. 10, 15-26. https://doi.org/10.1038/nrcardio.2012.158
  55. Wijffels, M.C., Kirchhof, C.J., Dorland, R., and Allessie, M.A. (1995). Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92, 1954-1968. https://doi.org/10.1161/01.CIR.92.7.1954
  56. Wilkes, M.C. and Leof, E.B. (2006). Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J. Biol. Chem. 281, 27846-27854. https://doi.org/10.1074/jbc.M603721200
  57. Wu, H., Chen, L., Xie, J., Li, R., Li, G.N., Chen, Q.H., Zhang, X.L., Kang, L.N., and Xu, B. (2016). Periostin expression induced by oxidative stress contributes to myocardial fibrosis in a rat model of high salt-induced hypertension. Mol. Med. Rep. 14, 776-782. https://doi.org/10.3892/mmr.2016.5308
  58. Xie, Y., Garfinkel, A., Camelliti, P., Kohl, P., Weiss, J.N., and Qu, Z. (2009). Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: a computational study. Heart Rhythm 6, 1641-1649. https://doi.org/10.1016/j.hrthm.2009.08.003
  59. Yamaguchi, Y. (2014). Periostin in skin tissue skin-related diseases. Allergol. Int. 63, 161-170. https://doi.org/10.2332/allergolint.13-RAI-0685
  60. Zhao, S., Wu, H., Xia, W., Chen, X., Zhu, S., Zhang, S., Shao, Y., Ma, W., Yang, D., and Zhang, J. (2014). Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts. J. Cardiol. 63, 373-378. https://doi.org/10.1016/j.jjcc.2013.09.013
  61. Zhao, Y., Wang, C., Wang, C., Hong, X., Miao, J., Liao, Y., Zhou, L., and Liu, Y. (2018). An essential role for Wnt/beta-catenin signaling in mediating hypertensive heart disease. Sci. Rep. 8, 8996. https://doi.org/10.1038/s41598-018-27064-2
  62. Zhong, H., Wang, T., Lian, G., Xu, C., Wang, H., and Xie, L. (2018). TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling. Heart Vessels 33, 1094-1105. https://doi.org/10.1007/s00380-018-1146-0
  63. Ziyadeh-Isleem, A., Clatot, J., Duchatelet, S., Gandjbakhch, E., Denjoy, I., Hidden-Lucet, F., Hatem, S., Deschenes, I., Coulombe, A., Neyroud, N., et al. (2014). A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation. Heart Rhythm 11, 1015-1023. https://doi.org/10.1016/j.hrthm.2014.02.021

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