【作者】Zhang, CM (Zhang, Caimei)1;Chen, BY (Chen, Biyi)1;Wang, YH (Wang, Yihui)1,2;Guo, A (Guo, Ang)1;Tang, YQ (Tang, Yiqun)1,3;Khataei, T (Khataei, Tahsin)1;Shi, Y (Shi, Yun)1;Kutschke, WJ (Kutschke, William J.)1;Zimmerman, K (Zimmerman, Kathy)4;Weiss, RM (Weiss, Robert M.)1
【作者单位】a Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States; b Shanghai First People\'s Hospital, Shanghai Jiaotong University, Shanghai, China; c Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; d Department of Veterans Affairs Medical Center, Iowa City, IA, United States; e Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China; f Department of Surgery, Ohio State University Medical Center, Columbus, OH, United States
【摘要】The cardiac transverse (T)-tubule membrane system is the safeguard for cardiac function and undergoes dramatic remodeling in response to cardiac stress. However, the mechanism by which cardiomyocytes repair damaged T-tubule network remains unclear. In the present study, we tested the hypothesis that MG53, a muscle-specific membrane repair protein, antagonizes T-tubule damage to protect against maladaptive remodeling and thereby loss of excitation-contraction coupling and cardiac function. Using MG53-knockout (MG53-KO) mice, we first established that deficiency of MG53 had no impact on maturation of the T-tubule network in developing hearts. Additionally, MG53 ablation did not influence T-tubule integrity in unstressed adult hearts as late as 10 months of age. Following left ventricular pressure overload-induced cardiac stress, MG53 protein levels were increased by approximately three-fold in wild-type mice, indicating that pathological stress induces a significant upregulation of MG53. MG53-deficient mice had worsened T-tubule disruption and pronounced dysregulation of Ca 2+ handling properties, including decreased Ca 2+ transient amplitude and prolonged time to peak and decay. Moreover, MG53 deficiency exacerbated cardiac hypertrophy and dysfunction and decreased survival following cardiac stress. Our data suggest MG53 is not required for T-tubule development and maintenance in normal physiology. However, MG53 is essential to preserve T-tubule integrity and thereby Ca 2+ handling properties and cardiac function under pathological cardiac stress.
