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김준철 (Joon-Chul Kim) 저자 이메일 보기
New York University School of Medicine
조회 650  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Disruption of Ca2+i Homeostasis and Cx43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in PKP2-Deficient Mice
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Background: Plakophilin-2 (PKP2) is classically defined as a desmosomal protein. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy (ARVC). A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events consequent to PKP2 deficiency. Here, we sought to capture early molecular/cellular events that can act as nascent arrhythmic/cardiomyopathic substrates.

Methods: We used multiple imaging, biochemical and high-resolution mass spectrometry methods to study functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice ("PKP2cKO") 14 days post-tamoxifen (post-TAM) injection, a time point preceding overt electrical or structural phenotypes. Myocytes from right or left ventricular free wall were studied separately.

Results: Most properties of PKP2cKO left ventricular (PKP2cKO-LV) myocytes were not different from control; in contrast, PKP2cKO right ventricular (PKP2cKO-RV) myocytes showed increased amplitude and duration of Ca2+ transients, increased [Ca2+] in the cytoplasm and sarcoplasmic reticulum (SR), increased frequency of spontaneous Ca2+ release events (sparks) even at comparable SR load, and dynamic Ca2+ accumulation in mitochondria. We also observed early- and delayed-after transients in RV myocytes and heightened susceptibility to arrhythmias in Langendorff-perfused hearts. In addition, RyR2 in PKP2cKO-RV cells presented enhanced Ca2+ sensitivity and preferential phosphorylation in a domain known to modulate Ca2+ gating. RNAseq at 14 days post-TAM showed no relevant difference in transcript abundance between RV and LV, neither in control nor in PKP2cKO cells. Instead, we found an RV-predominant increase in membrane permeability that can permit Ca2+ entry into the cell. Cx43 ablation mitigated the membrane permeability increase, accumulation of cytoplasmic Ca2+, increased frequency of sparks and early stages of RV dysfunction. Cx43 hemichannel block with GAP19 normalized [Ca2+]i homeostasis. Similarly, PKC inhibition normalized spark frequency at comparable SR load levels.

Conclusions: Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca2+ dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Cx43-dependent membrane conduit and repressed by PKC inhibitors. Given that asymmetric Ca2+ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca2+ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.

Keywords : connexin43 hemichannel, calcium homeostasis, PKP2, ARVC

- 형식: Research article
- 게재일: 2019년 07월 (BRIC 등록일 2019-07-30)
- 연구진: 국내+국외 연구진
- 분야: Medicine
관련 인터뷰
1. 논문관련 분야의 소개, 동향, 전망을 설명, 연구과정에서 생긴 에피소드 유전질환인 Plakophilin-2(PKP2) 단백 결핍 질환시, 심장 근조직 접합 손실로, Connexin 43 간극접합 구조 (세포-세포간 연결통로)가 해미채널 (짝이 해제된 간극접합 구조)로 분리되어, 이를 통로로 세포내로 칼슘이온이 유입되어 Sarcoplasmic Reticulum 칼슘저장소, 세포질, 미토콘드리아 칼슘 레벨이 과도해지고, 동시에 Protein Kinase...
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발표: 김종민 (POSTECH)
일자: 2020년 1월 6일 (월) 오후 02시 (한국시간)
언어: 영어
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일자: 2019년 12월 19일 (목) 오후 02시 (한국시간)
언어: 한국어
참석자 접수신청하기

  댓글 1
회원작성글 니케타스  (2019-09-19 18:02)
Charles 축하해.
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