| Autor: |
Li J; Department of Pharmacology and Toxicology, College of Pharmacy.; Nora Eccles Harrison Cardiovascular Research and Training Institute., Richmond B; Department of Pharmacology and Toxicology, College of Pharmacy., Cluntun AA; Department of Biochemistry., Bia R; Nora Eccles Harrison Cardiovascular Research and Training Institute., Walsh MA; College of Health, Department of Nutrition and Integrative Physiology, Program in Molecular Medicine., Shaw K; Department of Pharmacology and Toxicology, College of Pharmacy., Symons JD; College of Health, Department of Nutrition and Integrative Physiology, Program in Molecular Medicine.; Diabetes & Metabolism Research Center, and., Franklin S; Nora Eccles Harrison Cardiovascular Research and Training Institute., Rutter J; Department of Biochemistry.; College of Health, Department of Nutrition and Integrative Physiology, Program in Molecular Medicine.; Diabetes & Metabolism Research Center, and.; Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah, USA., Funai K; College of Health, Department of Nutrition and Integrative Physiology, Program in Molecular Medicine.; Diabetes & Metabolism Research Center, and., Shaw RM; Nora Eccles Harrison Cardiovascular Research and Training Institute., Hong T; Department of Pharmacology and Toxicology, College of Pharmacy.; Nora Eccles Harrison Cardiovascular Research and Training Institute.; Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah, USA. |
| Abstrakt: |
Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control. |
