Ion channels and cardiac disease: mechanisms and functions of a disintegrin and metalloproteases and their substrates.

Normal physiological activity of the heart depends on the coordinated regulation of various ion channels in cardiomyocytes (CM), and dysfunction of these channels serves as a key pathological basis for cardiac diseases, including arrhythmias and heart failure Mitochondria play a central role in maintaining the cardiac redox balance and calcium (Ca2+) homeostasis, and cardiac mitochondrial dysfunction constitutes a core mechanism underlying ion channel dysregulation and heart disease pathogenesis. A disintegrin and metalloproteinases (ADAMs) are a family of transmembrane proteases that play critical roles in cell adhesion, migration, and intercellular communication via the cleavage of diverse substrates on the plasma membrane. The abnormal expression of various bioactive ADAM family substrates and their hydrolysis are closely related to the occurrence of many cardiac diseases. Previous studies have shown that ADAMs and their substrates participate in the maintenance of cardiac Ca2+ homeostasis, action potential formation, and electrical signal transduction by affecting the expression, localization, and function of cardiac ion channels. This review systematically summarizes the regulatory effects of ADAMs and their substrates on cardiac ion channels and discusses their potential relationship with mitochondrial dysfunction and cardiac remodeling. We also summarize the current therapeutic drugs targeting cardiac ion channels, to provide potential strategies for mechanistic research and clinical interventions for heart disease.