voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart电压门控离子通道功能障碍之前心肌病发展瘠薄的心.pdfVIP

Voltage-Gated Ion Channel Dysfunction Precedes Cardiomyopathy Development in the Dystrophic Heart 1 2 1,2 1 1 1 Xaver Koenig , Sandra Dysek , Stefanie Kimbacher , Agnes K. Mike , Rene Cervenka , Peter Lukacs , 1 1 1 2 1 Katrin Nagl , Xuan B. Dang , Hannes Todt , Reginald E. Bittner , Karlheinz Hilber * 1 Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria, 2 Center for Anatomy and Cell Biology, Neuromuscular Research Department, Medical University of Vienna, Vienna, Austria Abstract Background: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage- gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology. Methodology/Principal Findings: To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency signif