Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy.
Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy.
Int J Mol Sci. 2019 May 15;20(10):2403. doi: 10.3390/ijms20102403.
Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by the progressive substitution of functional myocardium with noncontractile fibro-fatty tissue contributing to ventricular arrhythmias and sudden cardiac death. Cyclophilin A (CyPA) is a ubiquitous protein involved in several pathological mechanisms, which also characterize ACM (i.e., fibrosis, inflammation, and adipogenesis). Nevertheless, the involvement of CyPA in ACM cardiac remodeling has not been investigated yet. Thus, we first evaluated CyPA expression levels in the right ventricle (RV) tissue specimens obtained from ACM patients and healthy controls (HC) by immunohistochemistry. Then, we took advantage of ACM- and HC-derived cardiac mesenchymal stromal cells (C-MSC) to assess CyPA modulation during adipogenic differentiation. Interestingly, CyPA was more expressed in the RV sections obtained from ACM vs. HC subjects and positively correlated with the adipose replacement extent. Moreover, CyPA was upregulated at early stages of C-MSC adipogenic differentiation and was secreted at higher level over time in ACM- derived C-MSC. Our study provides novel ex vivo and in vitro information on CyPA expression in ACM remodeling paving the way for future C-MSC-based mechanistic and therapeutic investigations.
致心律失常性心肌病（ACM）是一种遗传性疾病，其特征是功能性心肌逐渐被非收缩性纤维脂肪组织替代，导致室性心律失常和心脏性猝死。亲环蛋白 A（CyPA）是一种广泛存在的蛋白，参与多种病理机制，这些机制也与 ACM 相关（即纤维化、炎症和脂肪生成）。然而，CyPA 是否参与 ACM 心脏重构尚未得到研究。因此，我们首先通过免疫组织化学评估了 ACM 患者和健康对照（HC）的右心室（RV）组织标本中的 CyPA 表达水平。然后，我们利用 ACM 和 HC 来源的心脏间充质基质细胞（C-MSC）来评估脂肪生成分化过程中的 CyPA 调节。有趣的是，与 HC 受试者相比，ACM 患者的 RV 切片中 CyPA 表达更高，且与脂肪替代程度呈正相关。此外，CyPA 在 C-MSC 脂肪生成分化的早期阶段上调，并随着时间的推移在 ACM 来源的 C-MSC 中以更高水平分泌。我们的研究提供了关于 ACM 重构中 CyPA 表达的新的离体和体外信息，为未来基于 C-MSC 的机制和治疗研究铺平了道路。
