Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb;47(2):480-491.
doi: 10.1002/cbin.11948. Epub 2022 Oct 23.

Inhibition of intermittent calcium-activated potassium channel (SK4) attenuates Ang II-induced hypertrophy of human-induced stem cell-derived cardiomyocytes via targeting Ras-Raf-MEK1/2-ERK1/2 and CN-NFAT signaling pathways

Hongyi Zhao  1   2   3 , Xi Wang  1   2   3 , Yanhong Tang  1   2   3 , Qingyan Zhao  1   2   3 , Congxin Huang  1   2   3
Affiliations

Inhibition of intermittent calcium-activated potassium channel (SK4) attenuates Ang II-induced hypertrophy of human-induced stem cell-derived cardiomyocytes via targeting Ras-Raf-MEK1/2-ERK1/2 and CN-NFAT signaling pathways

Hongyi Zhao et al. Cell Biol Int. 2023 Feb.

Abstract

Cardiac hypertrophy caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. The intermediate calcium-activated potassium channel (SK4) has been shown to be involved in the process of the inflammatory response, cell proliferation, and apoptosis. However, the role of SK4 in cardiac hypertrophy has not been elucidated. Cardiac hypertrophy in human-induced pluripotent stem cells-derived cardiomyocytes (HiPSC-CMs) was induced by Ang II. Cells were transfected with SK4 adenovirus or treated with SK4 inhibitor (TRAM-34). TUNEL staining was used to assess the levels of apoptosis. Real-time polymerase chain reaction and Western blot analysis were used to measure messenger RNA (mRNA) and protein levels, respectively. The present results showed that SK4 expression was upregulated in HiPSC-CMs stimulated by Ang II. The downregulation of SK4 by a specific inhibitor TRAM-34 markedly ameliorated cardiac hypertrophy (reflected by the mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II treatment. The action of SK4 in cardiac hypertrophy was mediated by Ras-Raf-mitogen-activated protein kinases 1/2 (MEK1/2)-extracellular-regulated protein kinases 1/2 (ERK1/2) and calcineurin (CN)-nuclear factors of activated T cells (NFAT) activation. Our studies demonstrated that inhibition of SK4 significantly alleviated cardiac hypertrophy induced by Ang II in hiPSC-CMs by targeting Ras-Raf-MEK1/2-ERK1/2 signaling and CN-NFAT signaling pathway. Our studies suggest that SK4 may serve as a potential therapeutic target that could delay hypertrophy.

Keywords: ERK1/2; SK4; cardiac hypertrophy; hiPSC-CMs.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

REFERENCES

    1. Chen, C. L., Liao, J. W., Hu, O. Y. P., & Pao, L. H. (2016). Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury. Archives of Toxicology, 90(9), 2249-2260. https://doi.org/10.1007/s00204-015-1607-5
    1. Diedrichs, H., Hagemeister, J., Chi, M., Boelck, B., Mμller-Ehmsen, J., & Schneider, C. (2007). Activation of the Calcineurin/NFAT signalling cascade starts early in human hypertrophic myocardium. Journal of International Medical Research, 35(6), 803-818. https://doi.org/10.1177/147323000703500609
    1. Dong, D. L., Bai, Y. L., & Cai, B. Z. (2016). Calcium-activated potassium channels: Potential target for cardiovascular diseases. Advances in Protein Chemistry and Structural Biology, 104, 233-261. https://doi.org/10.1016/bs.apcsb.2015.11.007
    1. Facundo, H. T., Brainard, R. E., Watson, L. J., Ngoh, G. A., Hamid, T., Prabhu, S. D., & Jones, S. P. (2012). O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy. American Journal of Physiology-Heart and Circulatory Physiology, 302(10), H2122-H2130. https://doi.org/10.1152/ajpheart.00775.2011
    1. Frey, N., & Olson, E. N. (2003). Cardiac hypertrophy: The good, the bad, and the ugly. Annual Review of Physiology, 65, 45-79. https://doi.org/10.1146/annurev.physiol.65.092101.142243

MeSH terms

LinkOut - more resources