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Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs
BACKGROUND: Although vasospastic angina (VSA) is known to be caused by coronary artery spasm, no study has fully elucidated the exact underlying mechanism. Moreover, in order to confirm VSA, patients should undergo invasive coronary angiography with spasm provocation test. Herein, we investigated th...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9938986/ https://www.ncbi.nlm.nih.gov/pubmed/36803875 http://dx.doi.org/10.1186/s40824-023-00345-2 |
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author | Yang, Han-Mo Lee, Joo-Eun Kim, Ju-Young You, Jihye Kim, Joonoh Lee, Hak Seung Yoo, Hee Min Kong, Min Gyu Han, Jung-Kyu Cho, Hyun-Jai Park, Kyung Woo Kang, Hyun-Jae Koo, Bon-Kwon Park, Young-Bae Kim, Hyo-Soo |
author_facet | Yang, Han-Mo Lee, Joo-Eun Kim, Ju-Young You, Jihye Kim, Joonoh Lee, Hak Seung Yoo, Hee Min Kong, Min Gyu Han, Jung-Kyu Cho, Hyun-Jai Park, Kyung Woo Kang, Hyun-Jae Koo, Bon-Kwon Park, Young-Bae Kim, Hyo-Soo |
author_sort | Yang, Han-Mo |
collection | PubMed |
description | BACKGROUND: Although vasospastic angina (VSA) is known to be caused by coronary artery spasm, no study has fully elucidated the exact underlying mechanism. Moreover, in order to confirm VSA, patients should undergo invasive coronary angiography with spasm provocation test. Herein, we investigated the pathophysiology of VSA using peripheral blood-derived induced pluripotent stem cells (iPSCs) and developed an ex vivo diagnostic method for VSA. METHODS AND RESULTS: With 10 mL of peripheral blood from patients with VSA, we generated iPSCs and differentiated these iPSCs into target cells. As compared with vascular smooth muscle cells (VSMCs) differentiated from iPSCs of normal subjects with negative provocation test, VSA patient-specific iPSCs-derived VSMCs showed very strong contraction in response to stimulants. Moreover, VSA patient-specific VSMCs exhibited a significant increase in stimulation-induced intracellular calcium efflux (Changes in the relative fluorescence unit [ΔF/F]; Control group vs. VSA group, 2.89 ± 0.34 vs. 10.32 ± 0.51, p < 0.01), and exclusively induced a secondary or tertiary peak of calcium efflux, suggesting that those findings could be diagnostic cut-off values for VSA. The observed hyperreactivity of VSA patient-specific VSMCs were caused by the upregulation of sarco/endoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) due to its enhanced small ubiquitin-related modifier (SUMO)ylation. This increased activity of SERCA2a was reversed by treatment with ginkgolic acid, an inhibitor of SUMOylated E1 molecules (pi/µg protein; VSA group vs. VSA + ginkgolic acid, 52.36 ± 0.71 vs. 31.93 ± 1.13, p < 0.01). CONCLUSIONS: Our findings showed that abnormal calcium handling in sarco/endoplasmic reticulum could be induced by the enhanced SERCA2a activity in patients with VSA, leading to spasm. Such novel mechanisms of coronary artery spasm could be useful for drug development and diagnosis of VSA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40824-023-00345-2. |
format | Online Article Text |
id | pubmed-9938986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-99389862023-02-20 Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs Yang, Han-Mo Lee, Joo-Eun Kim, Ju-Young You, Jihye Kim, Joonoh Lee, Hak Seung Yoo, Hee Min Kong, Min Gyu Han, Jung-Kyu Cho, Hyun-Jai Park, Kyung Woo Kang, Hyun-Jae Koo, Bon-Kwon Park, Young-Bae Kim, Hyo-Soo Biomater Res Research Article BACKGROUND: Although vasospastic angina (VSA) is known to be caused by coronary artery spasm, no study has fully elucidated the exact underlying mechanism. Moreover, in order to confirm VSA, patients should undergo invasive coronary angiography with spasm provocation test. Herein, we investigated the pathophysiology of VSA using peripheral blood-derived induced pluripotent stem cells (iPSCs) and developed an ex vivo diagnostic method for VSA. METHODS AND RESULTS: With 10 mL of peripheral blood from patients with VSA, we generated iPSCs and differentiated these iPSCs into target cells. As compared with vascular smooth muscle cells (VSMCs) differentiated from iPSCs of normal subjects with negative provocation test, VSA patient-specific iPSCs-derived VSMCs showed very strong contraction in response to stimulants. Moreover, VSA patient-specific VSMCs exhibited a significant increase in stimulation-induced intracellular calcium efflux (Changes in the relative fluorescence unit [ΔF/F]; Control group vs. VSA group, 2.89 ± 0.34 vs. 10.32 ± 0.51, p < 0.01), and exclusively induced a secondary or tertiary peak of calcium efflux, suggesting that those findings could be diagnostic cut-off values for VSA. The observed hyperreactivity of VSA patient-specific VSMCs were caused by the upregulation of sarco/endoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) due to its enhanced small ubiquitin-related modifier (SUMO)ylation. This increased activity of SERCA2a was reversed by treatment with ginkgolic acid, an inhibitor of SUMOylated E1 molecules (pi/µg protein; VSA group vs. VSA + ginkgolic acid, 52.36 ± 0.71 vs. 31.93 ± 1.13, p < 0.01). CONCLUSIONS: Our findings showed that abnormal calcium handling in sarco/endoplasmic reticulum could be induced by the enhanced SERCA2a activity in patients with VSA, leading to spasm. Such novel mechanisms of coronary artery spasm could be useful for drug development and diagnosis of VSA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40824-023-00345-2. BioMed Central 2023-02-18 /pmc/articles/PMC9938986/ /pubmed/36803875 http://dx.doi.org/10.1186/s40824-023-00345-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Yang, Han-Mo Lee, Joo-Eun Kim, Ju-Young You, Jihye Kim, Joonoh Lee, Hak Seung Yoo, Hee Min Kong, Min Gyu Han, Jung-Kyu Cho, Hyun-Jai Park, Kyung Woo Kang, Hyun-Jae Koo, Bon-Kwon Park, Young-Bae Kim, Hyo-Soo Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title | Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title_full | Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title_fullStr | Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title_full_unstemmed | Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title_short | Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs |
title_sort | identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived ipscs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9938986/ https://www.ncbi.nlm.nih.gov/pubmed/36803875 http://dx.doi.org/10.1186/s40824-023-00345-2 |
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