Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing

Wang, Youcheng; Yao, Yajun; Ma, Yazhe; He, Shanqing; Yang, Mei; Cao, Zhen; Liudi, Shiwen; Fu, Yuntao; Chen, Huiyu; Wang, Xi; Huang, Congxin; Zhao, Qingyan

doi:10.7150/ijms.69626

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Int J Med Sci 2022; 19(14):1995-2007. doi:10.7150/ijms.69626 This issue Cite

Research Paper

Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing

Youcheng Wang^1,2,3,4*, Yajun Yao^2,3,4*, Yazhe Ma^2,3,4*, Shanqing He^2,3,4, Mei Yang^2,3,4, Zhen Cao^2,3,4, Shiwen Liudi^2,3,4, Yuntao Fu^2,3,4, Huiyu Chen^2,3,4, Xi Wang^2,3,4, Congxin Huang^2,3,4, Qingyan Zhao^2,3,4✉

1. Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, China.
2. Department of Cardiology, Renmin Hospital of Wuhan University Wuhan City, Wuchang, Wuhan, China.
3. Cardiovascular Research Institute, Wuhan University, Wuhan, China.
4. Hubei Key Laboratory of Cardiology, Wuhan, China.
* These authors have contributed equally to this work and share first authorship.

Citation:

Wang Y, Yao Y, Ma Y, He S, Yang M, Cao Z, Liudi S, Fu Y, Chen H, Wang X, Huang C, Zhao Q. Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing. Int J Med Sci 2022; 19(14):1995-2007. doi:10.7150/ijms.69626. https://www.medsci.org/v19p1995.htm

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Abstract

Background: We previously found that intermediate conductance Ca²⁺-activated K⁺ channel (SK4) might be an important target in atrial fibrillation (AF).

Objective: To investigate the role of SK4 in AF maintenance.

Methods: Twenty beagles were randomly assigned to the sham group (n=6), pacing group (n=7), and pacing+TRAM-34 group (n=7). Rapid atrial pacing continued for 7 days in the pacing and TRAM-34 groups. During the pacing, the TRAM-34 group received TRAM-34 intravenous injection (10 mg/Kg) 3 times per day. Atrial fibroblasts isolated from canines were treated with angiotensin II or adenovirus carrying the SK4 gene (Ad-SK4) to overexpress SK4 channels.

Results: TRAM-34 treatment significantly suppressed the increased intra-atrial conducting time (CT) and AF duration in canines after rapid atrial pacing (P<0.05). Compared with the sham group, the expression of SK4 in atria was higher in the pacing group, which was associated with an increased number of myofibroblasts and levels of extracellular matrix in atrium (all P<0.05), and this effect was reversed by TRAM-34 treatment (all P<0.05). In atrial fibroblasts, the increased expression of SK4 induced by angiotensin II stimulation or Ad-SK4 transfection contributed to higher levels of P38, ERK1/2 and their downstream factors c-Jun and c-Fos, leading to the increased expression of α-SMA (all P<0.05), and all these increases were markedly reduced by TRAM-34 treatment.

Conclusion: SK4 blockade suppressed AF by attenuating cardiac fibroblast activity and atrial fibrosis, which was realized through not only a decrease in fibrogenic factors but also inhibition of fibrotic signaling pathways.

Keywords: intermediate conductance Ca²⁺-activated K⁺ channel, SK4, TRAM-34, atrial fibrillation, atrial fibrosis, atrial fibroblast

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APA

Wang, Y., Yao, Y., Ma, Y., He, S., Yang, M., Cao, Z., Liudi, S., Fu, Y., Chen, H., Wang, X., Huang, C., Zhao, Q. (2022). Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing. International Journal of Medical Sciences, 19(14), 1995-2007. https://doi.org/10.7150/ijms.69626.

ACS

Wang, Y.; Yao, Y.; Ma, Y.; He, S.; Yang, M.; Cao, Z.; Liudi, S.; Fu, Y.; Chen, H.; Wang, X.; Huang, C.; Zhao, Q. Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing. Int. J. Med. Sci. 2022, 19 (14), 1995-2007. DOI: 10.7150/ijms.69626.

NLM

CSE

Wang Y, Yao Y, Ma Y, He S, Yang M, Cao Z, Liudi S, Fu Y, Chen H, Wang X, Huang C, Zhao Q. 2022. Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing. Int J Med Sci. 19(14):1995-2007.

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