pp 1–8 | Cite as

Effect of doxycycline on chronic intermittent hypoxia-induced atrial remodeling in rats

  • K. Zhang
  • Z. Ma
  • W. Wang
  • R. Liu
  • Y. Zhang
  • M. Yuan
  • G. LiEmail author
Original articles



Atrial remodeling in the form of fibrosis is considered the basis in the development of atrial fibrillation (AF). The aim of this study was to investigate the effects of doxycycline on atrial remodeling induced by chronic intermittent hypoxia (CIH) and the mechanisms underlying such changes.


A total of 45 Sprague-Dawley rats were randomized into three groups: control group, CIH group, CIH with doxycycline treatment (CIH-D) group. A rat model of atrial remodeling was established by CIH and Masson staining was used to evaluate the extent of atrial fibrosis. We studied the expression levels of microRNA-1 (miR-1), microRNA-21 (miR-21), microRNA-29b (miR-29b), microRNA-30 (miR-30), microRNA-133a (miR-133a), microRNA-328 (miR-328), transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF). Atrial effective refractory period and AF inducibility were examined via isolated heart models of cardiac electrophysiology.


Compared with the control rats, CIH rats showed higher atrial interstitial collagen deposition, increased AF inducibility, and increased miR-1, miR-21, miR-133a, miR-328, TGF-β1, and CTGF levels. Treatment with doxycycline significantly attenuated CIH-induced atrial fibrosis, improved AF inducibility, and reduced miR-1, miR-21, miR-133a, miR-328, TGF-β1, and CTGF.


CIH induced significant atrial remodeling, which was attenuated by doxycycline in our rat model. These changes can be explained by the alterations initiated in the miR-133a/TGF-β1/CTGF pathway by doxycycline.


Atrial fibrillation Alpha-6-Deoxyoxytetracycline MicroRNAs Transforming growth factors Connective tissue growth factor 

Wirkung von Doxycyclin auf das durch chronische intermittierende Hypoxie induzierte atriale Remodeling bei Ratten



Atriales Remodeling in Form einer Fibrose wird als Basis für die Entstehung des Vorhofflimmerns (VF) angesehen. Ziel der vorliegenden Studie war es, die Wirkungen von Doxycyclin auf das durch chronische intermittierende Hypoxie (CIH) induzierte atriale Remodeling und die diesen Veränderungen zugrunde liegenden Mechanismen zu untersuchen.


Insgesamt wurden 45 Sprague-Dawley-Ratten randomisiert in 3 Gruppen eingeteilt: die Kontrollgruppe, die CIH-Gruppe, die CIH-plus-Doxycyclin-Gruppe (CIH-D). Ein Rattenmodell des atrialen Remodelings wurde durch CIH erzeugt, und zur Untersuchung des Ausmaßes der atrialen Fibrose wurde die Masson-Färbung eingesetzt. Die Autoren ermittelten den Grad der Expression von MicroRNA-1 (miR-1), MicroRNA-21 (miR-21), MicroRNA-29b (miR-29b), MicroRNA-30 (miR-30), MicroRNA-133a (miR-133a), MicroRNA-328 (miR-328), transformierendem Wachstumsfaktor β1 („transforming growth factor-β1“, TGF-β1) und Bindegewebewachstumsfaktor („connective tissue growth factor“, CTGF). Anhand isolierter Herzmodelle der kardialen Elektrophysiologie wurden die atriale effektive Refraktärzeit und die VF-Induzierbarkeit untersucht.


Im Vergleich zu den Ratten der Kontrollgruppe wiesen die CIH-Ratten eine stärkere interstitielle Kollagenablagerung, eine erhöhte VF-Induzierbarkeit und erhöhte Werte für miR-1, miR-21, miR-133a, miR-328, TGF-β1 und CTGF auf. Durch Behandlung mit Doxycyclin wurde die CIH-induzierte atriale Fibrose signifikant vermindert, auch die VF-Induzierbarkeit und die Werte für miR-1, miR-21, miR-133a, miR-328, TGF-β1 und CTGF wurden gesenkt.


Durch CIH wurde ein signifikantes atriales Remodeling induziert, welches mittels der Gabe von Doxycyclin im hier verwendeten Rattenmodell vermindert wurde. Diese Veränderungen lassen sich durch Einwirkungen von Doxycyclin auf den miR-133a/TGF-β1/CTGF-Signalweg erklären.


Vorhofflimmern Alpha-6-Deoxyoxytetracyclin MicroRNA Transformierende Wachstumsfaktoren Bindegewebewachstumsfaktor 



We thank Xue Liang and Ya Suo for excellent technical support.


National Natural Science Foundation of China (81570304); Tianjin Municipal Science and Technology Commission (13ZCDSY01400); Tianjin Applied Basic and Frontior Technology Research Project (15JCQNJC10200); Second Hospital of Tianjin medical university Central Laboratory Research Fund Project (2017ydey17).

Compliance with ethical guidelines

Conflict of interest

K. Zhang, Z. Ma, W. Wang, R. Liu, Y. Zhang, M. Yuan, and G. Li declare that they have no competing interests.

All national guidelines for keeping and handling laboratory animals have been complied with and the necessary approvals from the competent authorities have been obtained.


  1. 1.
    Schotten U, Verheule S, Kirchhof P, Goette A (2011) Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 91:265–325. CrossRefPubMedGoogle Scholar
  2. 2.
    Jalife J, Kaur K (2015) Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc Med 25:475–484. CrossRefPubMedGoogle Scholar
  3. 3.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. CrossRefPubMedGoogle Scholar
  4. 4.
    Wojciechowska A, Braniewska A, Kozar-Kamińska K (2017) MicroRNA in cardiovascular biology and disease. Adv Clin Exp Med 26:865–874. CrossRefPubMedGoogle Scholar
  5. 5.
    van den Berg NWE, Kawasaki M, Berger WR (2017) MicroRNas in atrial fibrillation: from expression signatures to functional implications. Cardiovasc Drugs Ther 31:345–365. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Santulli G, Iaccarino G, De Luca N, Trimarco B, Condorelli G (2014) Atrial fibrillation and microRNAs. Front Physiol 5:15–22. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hua XF, Li XH, Li MM, Zhang CY, Liu HJ, Sun T et al (2017) Doxycycline attenuates paraquat-induced pulmonary fibrosis by downregulating the TGF-beta signaling pathway. J Thorac Dis 9:4376–4386. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hackmann AE, Rubin BG, Sanchez LA, Geraghty PA, Thompson RW, Curci JA (2008) A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair. J Vasc Surg 48:519–526. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wang W, Zhang K, Li X, Ma Z, Zhang Y, Yuan M, Suo Y et al (2018) Doxycycline attenuates chronic intermittent hypoxia-induced atrial fibrosis in rats. Cardiovasc Ther. CrossRefPubMedGoogle Scholar
  10. 10.
    Hammond SM (2015) An overview of microRNAs. Adv Drug Deliv Rev 87:3–14. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shi KH, Tao H, Yang JJ, Wu JX, Xu SS, Zhan HY (2013) Role of microRNAs in atrial fibrillation: New insights and perspectives. Cell Signal 25:2079–2084. CrossRefPubMedGoogle Scholar
  12. 12.
    Doñate Puertas R, Jalabert A, Meugnier E, Euthine V, Chevalier P, Rome S (2018) Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation. PLoS ONE 13:e196666. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    van Middendorp LB, Kuiper M, Munts C, Wouters P, Maessen JG, van Nieuwenhoven FA et al (2017) Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart. Esc Heart Fail 4:241–251. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Liu Y, Liang Y, Zhang JF, Fu WM (2017) MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications. Exp Cell Res 354:65–70. CrossRefPubMedGoogle Scholar
  15. 15.
    Leask A, Holmes A, Abraham DJ (2002) Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep 4:136–142. CrossRefGoogle Scholar
  16. 16.
    Liu Q, Chu H, Ma Y, Wu T, Qian F, Ren X et al (2016) Salvianolic acid B attenuates experimental pulmonary fibrosis through inhibition of the TGF-beta signaling pathway. Sci Rep 6:27610. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kim KH, Park GT, Lim YB, Rue SW, Jung JC, Sonn JK et al (2004) Expression of connective tissue growth factor, a biomarker in senescence of human diploidfibroblasts, is up-regulated by transforming growth factor-beta-mediated signaling pathway. Biochem Biophys Res Commun 318:819–825. CrossRefPubMedGoogle Scholar
  18. 18.
    Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783. CrossRefPubMedGoogle Scholar
  19. 19.
    Kiryu M, Niwano S, Niwano H, Kishihara J, Aoyama Y, Fukaya H et al (2012) Angiotensin II-mediated up-regulation of connective tissue growth factor promotes atrial tissue fibrosis in the canine atrial fibrillation model. Europace 14:1206–1214. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Xu GJ, Gan TY, Tang BP, Chen ZH, Ailiman M, Zhou XH, Jiang T et al (2013) Changes in microRNAs expression are involved in age-related atrial structural remodeling and atrial fibrillation. Chin Med J (engl) 126:1458–1463Google Scholar
  21. 21.
    Angelini A, Li Z, Mericskay M, Decaux JF (2015) Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133a Axis. PLoS ONE 10:e139858. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M et al (2011) Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet 4:446–454. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiologythe Second Hospital of Tianjin Medical UniversityTianjinChina

Personalised recommendations