Zhang Baowei, Wu Yizhang, Yang Xingbo, Xiang Yaozu, Yang Bing
Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai 200120, PR China.
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 150 Jimo Road, Pudong, Shanghai 200120, PR China.
Biomed Pharmacother. 2023 Nov;167:115448. doi: 10.1016/j.biopha.2023.115448. Epub 2023 Sep 9.
Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition to common clinical and pathological features, ACM caused by mutant DSG2 has specific characteristics, manifesting as left ventricle involvement and a high risk of heart failure. Pathological studies have shown extensive cardiomyocyte necrosis, infiltration of immune cells, and fibrofatty replacement in both ventricles, as well as abnormal desmosome structures in the hearts of humans and mice with mutant DSG2-related ACM. Although desmosome dysfunction is a common pathway in the pathogenesis of mutant DSG2-related ACM, the mechanisms underlying this dysfunction vary among mutations. Desmosome dysfunction induces cardiomyocyte injury, plakoglobin dislocation, and gap junction dysfunction, all of which contribute to the initiation and progression of ACM. Additionally, dysregulated inflammation, overactivation of transforming growth factor-beta-1 signaling and endoplasmic reticulum stress, and cardiac metabolic dysfunction contribute to the pathogenesis of ACM caused by mutant DSG2. These features demonstrate that patients with mutant DSG2-related ACM should be managed individually and precisely based on the genotype and phenotype. Further studies are needed to investigate the underlying mechanisms and to identify novel therapies to reverse or attenuate the progression of ACM caused by mutant DSG2.
突变型桥粒芯糖蛋白2（DSG2）是致心律失常性心肌病（ACM）中第二常见的致病基因，约占ACM病例的10%。除了常见的临床和病理特征外，由突变型DSG2引起的ACM具有特定特征，表现为左心室受累和心力衰竭风险高。病理研究表明，在突变型DSG2相关ACM患者的心脏中，两心室均存在广泛的心肌细胞坏死、免疫细胞浸润和纤维脂肪替代，以及桥粒结构异常。虽然桥粒功能障碍是突变型DSG2相关ACM发病机制中的常见途径，但这种功能障碍的潜在机制因突变而异。桥粒功能障碍会诱导心肌细胞损伤、连环蛋白错位和缝隙连接功能障碍，所有这些都有助于ACM的发生和发展。此外，炎症失调、转化生长因子-β-1信号过度激活和内质网应激以及心脏代谢功能障碍也有助于突变型DSG2引起的ACM的发病机制。这些特征表明，对于突变型DSG2相关ACM患者，应根据基因型和表型进行个体化和精准管理。需要进一步研究以探讨潜在机制，并确定新的疗法来逆转或减轻突变型DSG2引起的ACM的进展。
