Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs
Abstract 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 investi...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2023-02-01
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| Series: | Biomaterials Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40824-023-00345-2 |
| _version_ | 1827333653850488832 |
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| author | Han-Mo Yang Joo-Eun Lee Ju-Young Kim Jihye You Joonoh Kim Hak Seung Lee Hee Min Yoo Min Gyu Kong Jung-Kyu Han Hyun-Jai Cho Kyung Woo Park Hyun-Jae Kang Bon-Kwon Koo Young-Bae Park Hyo-Soo Kim |
| author_facet | Han-Mo Yang Joo-Eun Lee Ju-Young Kim Jihye You Joonoh Kim Hak Seung Lee Hee Min Yoo Min Gyu Kong Jung-Kyu Han Hyun-Jai Cho Kyung Woo Park Hyun-Jae Kang Bon-Kwon Koo Young-Bae Park Hyo-Soo Kim |
| author_sort | Han-Mo Yang |
| collection | DOAJ |
| description | Abstract 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 Ca2+-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. |
| first_indexed | 2024-03-07T17:30:34Z |
| format | Article |
| id | doaj.art-eab3758d7e894c6388147a35d28e32cd |
| institution | Directory Open Access Journal |
| issn | 2055-7124 |
| language | English |
| last_indexed | 2024-03-07T17:30:34Z |
| publishDate | 2023-02-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Biomaterials Research |
| spelling | doaj.art-eab3758d7e894c6388147a35d28e32cd2024-03-02T18:06:36ZengAmerican Association for the Advancement of Science (AAAS)Biomaterials Research2055-71242023-02-0127111710.1186/s40824-023-00345-2Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCsHan-Mo Yang0Joo-Eun Lee1Ju-Young Kim2Jihye You3Joonoh Kim4Hak Seung Lee5Hee Min Yoo6Min Gyu Kong7Jung-Kyu Han8Hyun-Jai Cho9Kyung Woo Park10Hyun-Jae Kang11Bon-Kwon Koo12Young-Bae Park13Hyo-Soo Kim14Department of Internal Medicine, Seoul National University HospitalNational Research Laboratory for Stem Cell NicheNational Research Laboratory for Stem Cell NicheNational Research Laboratory for Stem Cell NicheNational Research Laboratory for Stem Cell NicheDepartment of Internal Medicine, Seoul National University HospitalBiometrology Group, Korea Research Institute of Standards and Science (KRISS)Department of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalDepartment of Internal Medicine, Seoul National University HospitalAbstract 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 Ca2+-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.https://doi.org/10.1186/s40824-023-00345-2Coronary artery spasmVasospastic anginaCalciumEx vivo diagnosis |
| spellingShingle | Han-Mo Yang Joo-Eun Lee Ju-Young Kim Jihye You Joonoh Kim Hak Seung Lee Hee Min Yoo Min Gyu Kong Jung-Kyu Han Hyun-Jai Cho Kyung Woo Park Hyun-Jae Kang Bon-Kwon Koo Young-Bae Park Hyo-Soo Kim Identification of cell-biologic mechanisms of coronary artery spasm and its ex vivo diagnosis using peripheral blood-derived iPSCs Biomaterials Research Coronary artery spasm Vasospastic angina Calcium Ex vivo diagnosis |
| 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 | Coronary artery spasm Vasospastic angina Calcium Ex vivo diagnosis |
| url | https://doi.org/10.1186/s40824-023-00345-2 |
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