DOI QR코드

DOI QR Code

교감신경절제술(RDN) 후 caspase-1과 interleukin-1β 활성화로 인해 유발된 염증성 급성심근손상

Renal Sympathetic Denervation Induces Acute Myocardial Inflammation through Activation of Caspase-1 and Interleukin-1β

  • 이동원 (부산대학교 의과대학 내과학교실, 신장내과) ;
  • 김일영 (부산대학교 의과대학 내과학교실, 신장내과) ;
  • 곽임수 (부산대학교 의과대학 내과학교실, 신장내과)
  • Lee, Dong Won (Division of Nephrology, Department of Internal Medicine, Pusan National University, School of Medicine) ;
  • Kim, Il Young (Division of Nephrology, Department of Internal Medicine, Pusan National University, School of Medicine) ;
  • Kwak, Ihm Soo (Division of Nephrology, Department of Internal Medicine, Pusan National University, School of Medicine)
  • 투고 : 2018.01.31
  • 심사 : 2018.02.22
  • 발행 : 2018.02.28

초록

원심성, 구심성 교감신경 신호는 고혈압 및 심부전의 발생과 밀접한 관련이 있다. 혈관 내 카테터를 이용한 교감신경절제술(RDM)은 난치성 고혈압의 대체치료로 시행되어 왔다. 시술과 관련하여 장기간 신장의 안정성에 대해서는 보고가 있었으나 단기간 심근의 안정성에 대한 연구 결과는 없었다. 저자들은 RDN 시술로 인한 교감신경차단 후 염증성 심근손상이 발생할 수 있음을 가정하여 실험으로 검증하고자 하였다. 25마리의 암컷돼지를 3군으로 나누고-정상대조군(n=5), Sham군(n=5), RDN 시술군(n=15)-RDN 시술군을 시술 후 sacrifice 시기에 따라 다시 세분하였다-시술 후 즉시 sacrifice한 RDN-0 (n=5), 시술 1주 후 sacrifice한 RDN-1 (n=5), 시술 2주 후 sacrifice한 RDN-2 (n=5). 조영제의 영향을 배제하기 위해 설정했던 Sham군과 정상대조군 간에는 의미있는 차이를 보이지 않았다. $IL-1{\beta}$, $TNF-{\alpha}$ 등의 염증 싸이토카인은 시술 1주 후 증가하여 2주째 감소하였다. 항염증 싸이토카인 IL-10은 시술 직후부터 증가하여 2주째 감소하였다. Inflammasome에 의해 위험신호(danger signal)를 전달받고 활성화되는 Caspase-1 및 inflammasome을 매개하는 도메인 ASC는 시술 직후 활성화되어 발현이 증가하였고 2주까지 지속되었다. 그러나 caspase-1을 매개할 것으로 추정되었던 NLRP3 inflammasome의 발현은 의미있는 차이를 보이지 않았다. RDN 시술에 의한 교감신경차단은 caspase-1, $IL-1{\beta}$ 등의 활성화에 의해 염증성 심근손상을 초래할 수 있으며 RDN 시술 후에는 그 위험성을 고려해야 하겠다. NLRP3 외에 다른 NLRP inflammasome pathway의 관련성에 대한 추가연구가 필요하다.

Efferent and afferent sympathetic nerves are closely related to the development of hypertension and heart failure. Catheter-based renal sympathetic denervation (RDN) is implemented as a strategy to treat resistant hypertension. We investigated whether RDN procedure causes inflammatory damage on myocardium in the early phase of sympathetic denervation. Twenty-five female swine were divided into 3 groups: normal control (Normal, n=5), sham-operated control (Sham, n=5), and RDN groups (RDN, n=15). The RDN group was further subdivided into 3 subgroups according to the time of sacrifice: immediately (RDN-0, n=5), 1 week (RDN-1, n=5), and 2 weeks (RDN-2, n=5) after RDN. There were no significant changes in the clinical parameters between the normal control and sham-operated group using contrast-media. In the myocardium, inflammatory cytokines, $IL-1{\beta}$ and $TNF-{\alpha}$ increased at the first week, and then decreased at the second week after RDN. Anti-inflammatory cytokine, IL-10 increased immediately, and then decreased at the second week after RDN. Caspase-1 activity and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression increased immediately after RDN until the second week. However, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein 3 (NLRP3) expression did not show any significant differences among the groups. The RDN can cause acute myocardial inflammation through activation of caspase-1 and $IL-1{\beta}$. We should pay attention to protecting against early inflammatory myocardial damage after RDN.

키워드

참고문헌

  1. Azizi, M., Sapoval, M., Gosse, P., Monge, M., Bobrie, G., Delsart, P., Midulla, M., Mounier-Vehier, C., Courand, P., Lantelme, P., Denolle, T., Dourmap-Collas, C., Trillaud, H., Pereira, H., Plouin, P. and Chatellier, G. Renal Denervation for Hypertension (DENERHTN) investigators. 2015. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 385, 1957-1965. https://doi.org/10.1016/S0140-6736(14)61942-5
  2. Barajas, L., Powers, K. and Wang, P. 1984. Innervation of the renal cortical tubules: a quantitative study. Am. J. Physiol. 247, F50-F60.
  3. Booth, L., Schlaich, M., Nishi, E., Yao, S., Xu, J., Ramchandra, R., Lambert, G. and May, C. 2015. Short-term effects of catheter-based renal denervation on cardiac sympathetic drive and cardiac baroreflex function in heart failure. Int. J. Cardiol. 190, 220-226. https://doi.org/10.1016/j.ijcard.2015.03.440
  4. Chobanian, A., Bakris, G., Black, H., Cushman, W., Green, L., Izzo, J. L. Jr., Jones, D., Materson, B., Oparil, S., Wright, J. Jr. and Roccella, E. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. 2003. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 289, 2560-2572. https://doi.org/10.1001/jama.289.19.2560
  5. Cutler, J., Sorlie, P., Wolz, M., Thom, T., Fields, L. and Roccella, E. 2008. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 1999-2004. Hypertension 52, 818-827. https://doi.org/10.1161/HYPERTENSIONAHA.108.113357
  6. DiBona, G. and Kopp, U. 1997. Neural control of renal function. Physiol. Rev. 77, 75-197. https://doi.org/10.1152/physrev.1997.77.1.75
  7. DiBona, G. 2005. Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R633-R641. https://doi.org/10.1152/ajpregu.00258.2005
  8. Dinarello, C. 1996. Biologic basis for interleukin-1 in disease. Blood 87, 2095-2147.
  9. Donazzan, L., Mahfoud, F., Ewen, S., Ukena, C., Cremers, B., Kirsch, C., Hellwig, D., Eweiwi, T., Ezziddin, S., Esler, M. and Bohm, M. 2016.ellH Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension. Clin. Res. Cardiol. 105, 364-371. https://doi.org/10.1007/s00392-015-0930-4
  10. Esler, M. 2000. The sympathetic system and hypertension. Am. J. Hypertens. 13, S99-S105.
  11. Elser, M., Rumantir, M., Kaye, D., Jennings, G., Hastings, J., Socratous, F. and Lambert, G. 2001. Sympathetic nerve biology in essential hypertension. Clin. Exp. Pharmacol. Physiol. 28, 986-989. https://doi.org/10.1046/j.1440-1681.2001.03566.x
  12. Esler, M. 2010. The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanism to medical management. J. Appl. Physiol. 108, 227-237.
  13. Esler, M., Krum, H., Sobotka, P., Schlaich, M., Schmieder, R. and Bohm, M. 2010. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 376, 1903-1909. https://doi.org/10.1016/S0140-6736(10)62039-9
  14. Fantuzzi, G., Puren, A., Harding, M., Livingston, D. and Dinarello, C. 1998. Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1 beta-converting enzyme (caspase-1)-deficient mice. Blood 91, 2118-2125.
  15. Franchi, L., Eigenbrod, T., Munoz-Planillo, R. and Nunez, G. 2009. The inflammasome: a caspase-1-activation paltform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241-247.
  16. Hu, J., Li, Y., Cheng, W., Yang, Z., Wang, F., Lv, P., Niu, C., Hou, Y., Yan, Y. and Ge, J. 2014. A comparison of the efficacy of surgical renal denervation and pharmacologic therapies in post-myocardial infarction heart failure. PLoS One 9, e96996. https://doi.org/10.1371/journal.pone.0096996
  17. Huang, B., Yu, L., He, B., Wang, S., Lu, Z., Liao, K., Wang, Z., Zhou, X., He, W. and Jiang, H. 2015. Sympathetic denervation of heart and kidney induces similar effects on ventricular electrophysiological properties. EuroIntervention 11, 598-604. https://doi.org/10.4244/EIJV11I5A119
  18. James, P., Oparil, S., Carter, B., Cushman, W., Dennison-Himmelfarb, C., Handler, J., Lackland, D., LeFevre, M., MacKenzie, T., Ogedegbe, O., Smith, S. Jr., Svetkey, L., Taler, S., Townsend, R., Wright, J. Jr., Narva, A. and Ortiz, E.. 2014. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 311, 507-520. https://doi.org/10.1001/jama.2013.284427
  19. Kiuchi, M. G., Chen, S., E. Silva, G. R., Paz, L. M., Kiuchi, T., de Paula Filho, A. G. and Souto, G. L. 2016. Pulmonary vein isolation alone and combined with renal sympathetic denervation in chronic kidney disease patients with refractory atrial fibrillation. Kidney Res. Clin. Pract. 35, 237-244. https://doi.org/10.1016/j.krcp.2016.08.005
  20. Kjeldsen, S., Fadl Elmula, F. and Persu, A. 2015. The setback of renal denervation should not backfire on sympathetic overactivity in hypertension. J. Am. Coll. Cardiol. 65, 1322-1323. https://doi.org/10.1016/j.jacc.2015.01.038
  21. Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P., Sadowski, J., Bartus, K., Kapelak, B., Walton, A., Sievert, H., Thambar, S., Abraham, W. T. and Esler, M. 2009. Catheter-based renal sympathetic denervation for resistant hypertension: multicentre safety and proof-of-principle cohort study. Lancet 373, 1275-1281. https://doi.org/10.1016/S0140-6736(09)60566-3
  22. Krum, H., Sobotka, P., Mahfoud, F., Bohm, M., Esler, M. and Schlaich, M. 2011. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. Circulation 123, 209-215. https://doi.org/10.1161/CIRCULATIONAHA.110.971580
  23. Li, Z., Jiang, H., Chen, D., Liu, Q., Geng, J., Guo, J., Sun, R., Zhu, G. and Shan, Q. 2015. Renal sympathetic denervation improves cardiac dysfunction in rats with chronic pressure overload. Physiol. Res. 64, 653-662.
  24. Sarafidis, P. and Bakris, G. 2008. Resistant hypertension, An overview of evaluation and treatment. J. Am. Coll. Cardiol. 52, 1749-1757. https://doi.org/10.1016/j.jacc.2008.08.036
  25. Schroder, K. and Tschopp, J. 2010. The inflammasomes. Cell 140, 821-832. https://doi.org/10.1016/j.cell.2010.01.040
  26. Schroder, K., Zhou, R. and Tschopp, J. 2010. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296-300. https://doi.org/10.1126/science.1184003
  27. Tsioufis, C., Papademetriou, V., Dimitriadis, K., Tsiachris, D., Thomopoulos, C., Park, E., Hata, C., Papalois, A. and Stefanadis, C. 2013. Catheter-based renal sympathetic denervation exerts acute and chronic effects on renal hemodynamics in swine. Int. J. Cardiol. 168, 987-992. https://doi.org/10.1016/j.ijcard.2012.10.038
  28. Zheng, X., Li, X., Lyu, Y., He, Y., Wan, W., Zhu, H. and Jiang, X. 2016. Possible mechanism by which renal sympathetic denervation improves left ventricular remodeling after myocardial infarction. Exp. Physiol. 101, 260-271. https://doi.org/10.1113/EP085302