Department of Medical and Surgical Sciences, Magna Græcia University, 88100 Catanzaro, Italy.
Department of Clinical and Experimental Medicine, Magna Græcia University, 88100 Catanzaro, Italy.
Int J Mol Sci. 2021 Feb 18;22(4):2004. doi: 10.3390/ijms22042004.
Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is an inherited cardiac muscle disease linked to genetic deficiency in components of the desmosomes. The disease is characterized by progressive fibro-fatty replacement of the right ventricle, which acts as a substrate for arrhythmias and sudden cardiac death. The molecular mechanisms underpinning ARVC are largely unknown. Here we propose a mathematical model for investigating the molecular dynamics underlying heart remodeling and the loss of cardiac myocytes identity during ARVC. Our methodology is based on three computational models: firstly, in the context of the Wnt pathway, we examined two different competition mechanisms between β-catenin and Plakoglobin (PG) and their role in the expression of adipogenic program. Secondly, we investigated the role of RhoA-ROCK pathway in ARVC pathogenesis, and thirdly we analyzed the interplay between Wnt and RhoA-ROCK pathways in the context of the ARVC phenotype. We conclude with the following remark: both Wnt/β-catenin and RhoA-ROCK pathways must be inactive for a significant increase of expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis.
致心律失常性右心室心肌病（ARVC）是一种遗传性心肌疾病，与桥粒成分的基因缺失有关。该疾病的特征是右心室进行性纤维脂肪替代，这是心律失常和心脏性猝死的基础。ARVC 的分子机制在很大程度上尚不清楚。在这里，我们提出了一个数学模型，用于研究 ARVC 中心脏重构和心肌细胞丧失特征的分子动力学。我们的方法基于三个计算模型：首先，在 Wnt 途径的背景下，我们研究了β-catenin 和 Plakoglobin（PG）之间的两种不同竞争机制及其在脂肪生成程序表达中的作用。其次，我们研究了 RhoA-ROCK 途径在 ARVC 发病机制中的作用，第三，我们分析了 Wnt 和 RhoA-ROCK 途径在 ARVC 表型中的相互作用。我们得出以下结论：Wnt/β-catenin 和 RhoA-ROCK 途径都必须失活，才能使 表达显著增加，这表明可能存在一种串扰机制负责介导 ARVC 的发病机制。
