한빛사논문
- 조회348
Han‑Mo Yang1,2,3†, Joo‑Eun Lee2,3†, Ju‑Young Kim2,3, Jihye You2,3, Joonoh Kim2,3, Hak Seung Lee1,2,3, Hee Min Yoo4, Min Gyu Kong1,5, Jung‑Kyu Han1,2,3, Hyun‑Jai Cho1,2,3, Kyung Woo Park1,2,3, Hyun‑Jae Kang1,2,3, Bon‑Kwon Koo1,2,3, Young‑Bae Park1,2,3 and Hyo‑Soo Kim1,2,3,6*
1Department of Internal Medicine, Seoul National University Hospital, 101 Daekak‑Ro, Chongno‑Gu, Seoul 03080, Korea
2National Research Laboratory for Stem Cell Niche, Seoul, Korea
3Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
4Biometrology Group, Korea Research Institute of Standards and Science(KRISS), Daejeon, Korea
5Department of Internal Medicine, Soon Chun Hyang University Hospital, Bucheon, Korea
6Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 03080, Korea
†Han-Mo Yang and Joo-Eun Lee contributed equally to this work.
*Corresponding author: Correspondence to Hyo-Soo Kim.
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.
논문정보
- Research article
- 2023년 02월 (BRIC 등록일 2023-02-22)
- 국내 연구진
- 의약학 > 응용의학
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