Abstract
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.
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Change history
14 March 2020
There was a mistake of IL-6 blot in the Fig. 5 in the present paper, and authors had mistakenly pasted the blot of Bax for IL-6 when making Figure5.
14 March 2020
There was a mistake of IL-6 blot in the Fig. 5 in the present paper, and authors had mistakenly pasted the blot of Bax for IL-6 when making Figure5.
Abbreviations
- AF:
-
Atrial fibrillation
- AMPK:
-
AMP-activated protein kinase
- ATP:
-
Adenosine triphosphate
- AERP:
-
Atrial effective refractory period
- BAX:
-
Bcl-2-associated X Protein
- Bcl-2:
-
B cell lymphoma-2
- CIA:
-
Collagen-induced arthritis
- FAT/CD36:
-
Fatty acid translocase/cluster of differentiation 36
- FFA:
-
Free fatty acid
- GLUT4:
-
Glucose transporter 4
- IL-6:
-
Interleukin-6
- PGC-1α:
-
PPAR co-activator 1α
- RA:
-
Rheumatoid arthritis
- TNF-α:
-
Tumor necrosis factor-α
- TUNEL:
-
Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling
References
Bacani AK, Crowson CS, Roger VL, Gabriel SE, Matteson EL (2015) Increased incidence of atrial fibrillation in patients with rheumatoid arthritis. Biomed Res Int 2015:809514
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285
Chen F, Chen D, Zhao X, Yang S, Li Z, Sanchis D, Jin L, Qiang X, Wang K, Xu Y, Zhang Y, Ye J (2017) Interleukin-6 deficiency facilitates myocardial dysfunction during high fat diet-induced obesity by promoting lipotoxicity and inflammation. Biochim Biophys Acta 1863:3128–3141
Chiang MC, Nicol CJ, Cheng YC (2017) Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress. Neurochem Int 115:1–10
Chong E, Chang SL, Hsiao YW, Singhal R, Liu SH, Leha T, Lin WY, Hsu CP, Chen YC, Chen YJ, Wu TJ, Higa S, Chen SA (2015) Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation. Heart Rhythm 12:1046–1056
Dai H, Wang X, Yin S, Zhang Y, Han Y, Yang N, Xu J, Sun L, Yuan Y, Sheng L, Gong Y, Li Y (2017) Atrial fibrillation promotion in a rat model of rheumatoid arthritis. J Am Heart Assoc 6(12):e007320
Diness JG, Skibsbye L, Jespersen T, Bartels ED, Sorensen US, Hansen RS, Grunnet M (2011) Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition. Hypertension 57:1129–1135
Hao L, Wan Y, Xiao J, Tang Q, Deng H, Chen L (2017) A study of Sirt1 regulation and the effect of resveratrol on synoviocyte invasion and associated joint destruction in rheumatoid arthritis. Mol Med Rep 16:5099–5106
Harada M, Nattel SN, Nattel S (2012) AMP-activated protein kinase: potential role in cardiac electrophysiology and arrhythmias. Circ Arrhythm Electrophysiol 5(4):860–867
Harada M, Tadevosyan A, Qi X, Xiao J, Liu T, Voigt N, Karck M, Kamler M, Kodama I, Murohara T, Dobrev D, Nattel S (2015) Atrial fibrillation activates AMP-dependent protein kinase and its regulation of cellular calcium handling: potential role in metabolic adaptation and prevention of progression. J Am Coll Cardiol 66:47–58
Hu YF, Chen YJ, Lin YJ, Chen SA (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12:230–243
Jäger S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104:12017–12022
Kim SC, Liu J, Solomon DH (2014) The risk of atrial fibrillation in patients with rheumatoid arthritis. Ann Rheum Dis 73:1091–1095
Kitas GD, Gabriel SE (2011) Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 70:8–14
Klingenberg R, Lüscher TF (2015) Rheumatoid arthritis and coronary atherosclerosis: two cousins engaging in a dangerous liaison. Eur Heart J 36:3423–3425
Lazúrová I, Tomáš Ľ (2017) Cardiac impairment in rheumatoid arthritis and influence of anti-TNFα treatment. Clin Rev Allergy Immunol 52:323–332
Lenski M, Schleider G, Kohlhaas M, Adrian L, Adam O, Tian Q, Kaestner L, Lipp P, Lehrke M, Maack C, Böhm M, Laufs U (2015) Arrhythmia causes lipid accumulation and reduced glucose uptake. Basic Res Cardiol 110:40
Li Y, Shi J, Yang BF, Liu L, Han CL, Li WM, Dong DL, Pan ZW, Liu GZ, Geng JQ, Sheng L, Tan XY, Sun DH, Gong ZH, Gong YT (2012) Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol. Br J Pharmacol 165:1748–1756
Li W, Yan S, Zhao J, Ding X, Zhang S, Wang D, Liu L, Peng W, Li H, Wang D, Liu Z, Li Y (2015) Metoprolol inhibits cardiac apoptosis and fibrosis in a canine model of chronic obstructive sleep apnea. Cell Physiol Biochem 36:1131–1141
Liew R, Khairunnisa K, Gu Y, Tee N, Yin NO, Naylynn TM, Moe KT (2013) Role of tumor necrosis factor-α in the pathogenesis of atrial fibrosis and development of an arrhythmogenic substrate. Circ J 77:1171–1179
Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Svendsen JH, Torp-Pedersen C, Hansen PR (2012) Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 344:e1257
Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 343:1594–1602
Liu GZ, Hou TT, Yuan Y, Hang PZ, Zhao JJ, Sun L, Zhao GQ, Zhao J, Dong JM, Wang XB, Shi H, Liu YW, Zhou JH, Dong ZX, Liu Y, Zhan CC, Li Y, Li WM (2016) Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway. Br J Pharmacol 173:1095–1109
Liu G, Wu K, Zhang L, Dai J, Huang W, Lin L, Ge P, Luo F, Lei H (2017) Metformin attenuated endotoxin-induced acute myocarditis via activating AMPK. Int Immunopharmacol 47:166–172
Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY, Vesey DA, Fairlie DP (2012) An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J 26:2877–2887
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Source 8th edition. Washington (DC): National Academies Press (US); 2011
Opacic D, van Bragt KA, Nasrallah HM, Schotten U, Verheule S (2016) Atrial metabolism and tissue perfusion as determinants of electrical and structural remodelling in atrial fibrillation. Cardiovasc Res 109:527–541
Palomer X, Alvarez-Guardia D, Rodríguez-Calvo R et al (2009) TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res 81:703–712
Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J 17:1975–1985
Qiu J, Zhou S, Liu Q (2016) Energy metabolic alterations in the progression of atrial fibrillation: potential role of AMP-activated protein kinase as a critical regulator. Int J Cardiol 212:14–15
Ravens U, Poulet C, Wettwer E, Knaut M (2013) Atrial selectivity of antiarrhythmic drugs. J Physiol 591:4087–4097
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388:2023–2038
Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, Yuan Y, Wang D, Ding X, Liu G, Li W, Zhao X, Liu Z, Li Y (2015) Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab 309:E925–E935
Suwa M, Nakano H, Kumagai S (2003) Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol (1985) 95:960–968
Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I (2002) Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem Biophys Res Commun 296:350–354
Ungprasert P, Srivali N, Kittanamongkolchai W (2017) Risk of incident atrial fibrillation in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int J Rheum Dis 20:434–441
Wahba MG, Messiha BA, Abo-Saif AA (2016) Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats. Pharm Biol 54:1705–1715
Wallace CH, Baczkó I, Jones L, Fercho M, Light PE (2006) Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. Br J Pharmacol 149:657–665
Wang X, Zhang Y (2018) Resveratrol alleviates LPS-induced injury in human keratinocyte cell line HaCaT by up-regulation of miR-17. Biochem Biophys Res Commun 501:106–112
Wang S, Wang Y, Zhang Z, Liu Q, Gu J (2017) Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway. Cell Death Dis 8:e3018
Xu K, Liu XF, Ke ZQ, Yao Q, Guo S, Liu C (2018) Resveratrol modulates apoptosis and autophagy induced by high glucose and palmitate in cardiac cells. Cell Physiol Biochem 46:2031–2040
Yang L, Zhang Y, Zhu M, Zhang Q, Wang X, Wang Y, Zhang J, Li J, Yang L, Liu J, Liu F, Yang Y, Kang L, Shen Y, Qi Z (2016) Resveratrol attenuates myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B. Free Radic Biol Med 101:1–9
Zhang Y, Wang YT, Shan ZL, Guo HY, Guan Y, Yuan HT (2015) Role of inflammation in the initiation and maintenance of atrial fibrillation and the protective effect of atorvastatin in a goat model of aseptic pericarditis. Mol Med Rep 11:2615–2623
Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 97:1784–1789
Funding
This work was financially supported by grants from the National Nature Scientific Foundation of China (no.81300133, no.81470462).
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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.
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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.
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The authors declare that they have no conflict of interest.
Electronic supplementary material
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)
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)
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Zhang, Y., Zhang, S., Liu, Z. et al. Resveratrol prevents atrial fibrillation by inhibiting atrial structural and metabolic remodeling in collagen-induced arthritis rats. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1179–1190 (2018). https://doi.org/10.1007/s00210-018-1554-9
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DOI: https://doi.org/10.1007/s00210-018-1554-9