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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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

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

Zusammenfassung

Hintergrund

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.

Methoden

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.

Ergebnisse

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.

Schlussfolgerung

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.

Schlüsselwörter

Vorhofflimmern Alpha-6-Deoxyoxytetracyclin MicroRNA Transformierende Wachstumsfaktoren Bindegewebewachstumsfaktor 

Notes

Acknowledgements

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

Funding

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.

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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

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