Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC.
Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC.
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DOI：
10.3390/jpm12101680
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发表时间：
2022-10-09
影响因子：
--
通讯作者：
Laurita, Kenneth R.
中科院分区：
文献类型：
--
作者：
Vasireddi, Sunil K.;Sattayaprasert, Prasongchai;Yang, Dandan;Dennis, Adrienne T.;Bektik, Emre;Fu, Ji-Dong;Mackall, Judith A.;Laurita, Kenneth R.
关键词：
致心律失常性右心室心肌病（ARVC）是桥粒和结构蛋白的遗传性疾病，其特征在于心室中的纤维脂肪浸润和可在显著结构异常之前早期发生的致命性心律失常。大多数ARVC突变干扰β-连环蛋白依赖性转录，从而增强脂肪生成;然而，脂肪生成的机制途径尚不清楚。我们假设脂肪形成条件在ARVC心律失常底物的形成中起重要作用。与间充质干细胞（MSC）共培养2-4天的心肌细胞单层衍生自具有ARVC 5 TMEM 43 p.Ser358Leu突变的人诱导多能干细胞。单独在肌细胞共培养物中的TMEM 43突变对脉冲传导速度（CV）或APD没有显著影响。相比之下，当共培养物暴露于促脂肪形成因子2-4天时，CV和APD与对照相比分别显著降低49%和31%，没有脂肪形成的证据。此外，这些心律失常底物与MSC中IGF-1表达的显著降低相一致，并且通过IGF-1治疗减轻。这些发现表明，增强的脂肪形成信号的开始可能是早期乳腺癌发生的机制，这可能导致与TMEM 43和其他ARVC突变相关的心律失常的个性化治疗。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin–dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2–4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2–4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations.
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影响因子：
24
作者：
James, Cynthia A.;Bhonsale, Aditya;Tichnell, Crystal;Murray, Brittney;Russell, Stuart D.;Tandri, Harikrishna;Tedford, Ryan J.;Judge, Daniel P.;Calkins, Hugh
通讯作者：
Calkins, Hugh
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.4
作者：
Andrews, Christopher M.;Srinivasan, Neil T.;Rudy, Yoram
通讯作者：
Rudy, Yoram
影响因子：
10.8
作者：
Djouadi, Fatima;Lecarpentier, Yves;Coirault, Catherine
通讯作者：
Coirault, Catherine
影响因子：
12.6
作者：
Dou, Wenkun;Zhao, Qili;Sun, Yu
通讯作者：
Sun, Yu