한빛사논문
- 조회640
Minjun Kang1,2,3*, Choon-Soo Lee1,3*, HyunJu Son1,3*, Jeongha Lee4, Jaewon Lee3, Hyun Ju Seo1,3, Moo-Kang Kim3, Murim Choi4, Hyun-Jai Cho2, Hyo-Soo Kim1,2,3
1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine or College of Pharmacy, Seoul National University, South Korea (M.K., C.-S.L., H.S., H.J.S., H.-S.K.).
2Department of Internal Medicine (M.-K.K., H.-J.C., H.-S.K.), Seoul National University Hospital, South Korea.
3Biomedical Research Institute (M.K., C.-S.L., H.S., Jaewon Lee, H.J.S., M.-K.K., H.-S.K.), Seoul National University Hospital, South Korea.
4Department of Biomedical Sciences, Seoul National University College of Medicine, South Korea (Jeongha Lee, M.C.).
*M. Kang, C.-S. Lee, and H. Son contributed equally.
Correspondence to: Hyun-Jai Cho, MD, PhD, Hyo-Soo Kim, MD, PhD
Abstract
Background: Latrophilin-2 (Lphn2), an adhesive GPCR (G protein-coupled receptor), was found to be a specific marker of cardiac progenitors during the differentiation of pluripotent stem cells into cardiomyocytes or during embryonic heart development in our previous studies. Its role in adult heart physiology, however, remains unclear.
Methods: The embryonic lethality resulting from Lphn2 deletion necessitates the establishment of cardiomyocyte-specific, tamoxifen-inducible Lphn2 knockout mice, which was achieved by crossing Lphn2flox/flox mice with mice having MerCreMer (tamoxifen-inducible Cre recombinase) under the α-myosin heavy chain promoter.
Results: Tamoxifen treatment for several days completely suppressed Lphn2 expression, specifically in the myocardium, and induced the dilated cardiomyopathy (D-CMP) phenotype with serious arrhythmia and sudden death in a short period of time. Transmission electron microscopy showed mitochondrial abnormalities, blurred Z-discs, and dehiscent myofibrils. The D-CMP phenotype, or heart failure, worsened during myocardial infarction. In a mechanistic study of D-CMP, Lphn2 knockout suppressed PGC-1α and mitochondrial dysfunction, leading to the accumulation of reactive oxygen species and the global suppression of junctional molecules, such as N-cadherin (adherens junction), DSC-2 (desmocollin-2; desmosome), and connexin-43 (gap junction), leading to the dehiscence of cardiac myofibers and serious arrhythmia. In an experimental therapeutic trial, activators of p38-MAPK, which is a downstream signaling molecule of Lphn2, remarkably rescued the D-CMP phenotype of Lphn2 knockout in the heart by restoring PGC-1α and mitochondrial function and recovering global junctional proteins.
Conclusions: Lphn2 is a critical regulator of heart integrity by controlling mitochondrial functions and cell-to-cell junctions in cardiomyocytes. Its deficiency leads to D-CMP, which can be rescued by activators of the p38-MAPK pathway.
논문정보
- Research article
- 2024년 10월 (BRIC 등록일 2024-10-21)
- 국내 연구진
- 의약학 > 응용의학
관련 웨비나
![심근병증의 새로운 기전 제시 : 심근세포내 라트로필린-2 결손에 의한 세포접합 붕괴 [Circ. Res.]](/upload/board/files/onseminar/thumb/thumb_0000819.png)
학술웨비나
심근병증의 새로운 기전 제시 : 심근세포내 라트로필린-2 결손에 의한 세포접합 붕괴 [Circ. Res.] 심장 기능을 조절하는 유전적 요인을 이해하는 것은 치료법 발전을 위해 필수적입니다. 이전 연구에서 접착 G 단백질 결합 수용체인 Latrophilin-2 (Lphn2)는 다능성 줄기세포에서 심근세포로 분화하거나 배아 심장 발달 과정에서 심장 전구체 세포의 특이적 표지자로 보고되었습니다. 그러나 성체 심장에서의 역할은 아직 불분명합니다. Lphn2 결손에 따른 배아 치사를 극복하기 위해, 우리는 타목시펜(Tamoxifen) 유도성, 심근세포 특이적 Lphn2 조건부 knock-out 마우스를 제작하여, 형질 분석을 보고 하여 심근병증의 새로운 기전을 제시하고, 임상적 유의성도 암시합니다.- 강민준(서울대학교병원)
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