Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 11, pp 1179–1190 | Cite as

Resveratrol prevents atrial fibrillation by inhibiting atrial structural and metabolic remodeling in collagen-induced arthritis rats

  • Yun Zhang
  • Song Zhang
  • Zonghong Liu
  • Xinbo Zhao
  • Yue Yuan
  • Li Sheng
  • Yue LiEmail author
Original Article


Rheumatoid arthritis (RA) causes atrial remodeling that induces the occurrence and maintenance of atrial fibrillation (AF). In this study, we explored the influence of RA on atrial fibrillation and the potential therapeutic effects of resveratrol in a rat model. The following three groups of female Wistar rats (8 weeks old) were used in this study: control, collagen-induced arthritis (CIA), and resveratrol. Rats in the CIA and resveratrol groups were injected twice with type II collagen in Freund’s incomplete adjuvant. Three weeks after the second injection, resveratrol (10 mg kg−1 day−1) was administered for 4 weeks. Subsequently, atrial electrophysiological parameters were measured. Levels of inflammatory factors in the atria and serum were measured. Atrial histopathological changes were assessed using microscopy, and cardiomyocyte apoptosis and fibrosis were assessed using TUNEL and Masson’s staining. Apoptosis-related and fibrosis-related proteins were assessed using Western blotting. Atrial adenosine triphosphate (ATP) and free fatty acid (FFA) levels were tested using ELISA. Glycogen accumulation and metabolism-related protein expression were assessed. AF inducibility and duration were markedly increased in CIA rats and were reduced by resveratrol. CIA also increased the atrial and serum IL-6 and TNF-a levels and induced atrial apoptosis and fibrosis, which were attenuated by resveratrol. Moreover, CIA induced the impairment of atrial energy metabolism by inhibiting the AMPK/PGC-1α pathway, which was reversed by resveratrol. Resveratrol protects against RA-induced atrial structural and metabolic remodeling, which may provide a new potential therapeutic treatment for RA-related AF.


Atrial fibrillation Atrial remodeling Fibrosis Apoptosis Rheumatoid arthritis Resveratrol 



Atrial fibrillation


AMP-activated protein kinase


Adenosine triphosphate


Atrial effective refractory period


Bcl-2-associated X Protein


B cell lymphoma-2


Collagen-induced arthritis


Fatty acid translocase/cluster of differentiation 36


Free fatty acid


Glucose transporter 4




PPAR co-activator 1α


Rheumatoid arthritis


Tumor necrosis factor-α


Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling


Authors’ contributions

Y. Z. and S. Z. designed and conducted the experiments, analyzed the data and wrote the manuscript. Y. Z., S. Z., Z. H. L., X. B. Z., Y. Y., and L. S. conducted the experiments. Y. L. designed the experiment and revised the manuscript. All authors approved the final version of the manuscript.


This work was financially supported by grants from the National Nature Scientific Foundation of China (no.81300133, no.81470462).

Compliance with ethical standards

All the protocols conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (the 8th Edition, NRC 2011) and were approved by the Experimental Animals Ethics Committee in Harbin Medical University.

Conflicts of interest

The authors declare that they have no conflict of interest.

Supplementary material

210_2018_1554_Fig8_ESM.png (70 kb)
Figure S1

Resveratrol reduces the serum level of systemic TNF-α and IL-6 induced by CIA. (A and B) The quantification of the serum levels of systemic TNF-α and IL-6 in all groups of rats is shown. The data are presented as the means ±standard deviation. *P < 0.05, ***P < 0.001 compared with the control group; #P < 0.05, ###P < 0.001 compared with the CIA group, n = 10 per group. (PNG 69 kb)

210_2018_1554_MOESM1_ESM.tif (2.1 mb)
High Resolution Image (TIF 2129 kb)
210_2018_1554_Fig9_ESM.png (825 kb)
Figure S2

Resveratrol suppresses CIA development and protects against joint destruction. (A) The quantification and statistical results for the DAI scores in all groups of rats are shown. The data are presented as the means ±standard deviation. *P < 0.05, **P < 0.01 compared with the CIA group, n = 10 per group. (B) Photographs of the hind paws and fore paws three weeks after the second injection are shown. DAI, disease activity index; CIA, collagen-induced arthritis; REV, resveratrol. (PNG 824 kb)

210_2018_1554_MOESM2_ESM.tif (8.9 mb)
High Resolution Image (TIF 9141 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Key Laboratory of Cardiac Diseases and Heart FailureHarbin Medical UniversityHarbinChina
  3. 3.Institute of Metabolic DiseaseHeilongjiang Academy of Medical ScienceHarbinChina

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