Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
View: Text | PDF
Research Article Cardiology Cell biology

Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose

Abstract

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.

Authors

Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong

×

Figure 1

cBIN1 is downregulated in diabetic mouse hearts and can be rescued by AAV9-cBIN1 to improve exercise capacity and systemic blood glucose control.

Options: View larger image (or click on image) Download as PowerPoint
cBIN1 is downregulated in diabetic mouse hearts and can be rescued by AA...
(A) Schematic illustration of experimental protocol used. (B) Western blots of cBIN1 and GAPDH with quantification (cBIN1/GAPDH) in heart lysates from posttreatment mice (n = 15 per group). (C–F) Bar graphs of plasma cBIN1 score (CS) values (n = 11–16, C), maximal running distance (n = 16–28, D), nonfasting plasma glucose (n = 9–17, E), and insulin (n = 9–16, F) in 9-week-old pretreatment (left) and 17-week-old posttreatment (right) db/db and littermate control db/m mice. (G) Percent of peak blood glucose during iGTT in AAV9-treated mice at 17 weeks of age (n = 4–6 animals per group). (H) Percent of baseline blood glucose during iITT in AAV9-treated mice at 17 weeks of age (n = 4–6 animals per group). (I) qPCR analysis of V5-tagged exogenous cBin1 (V5 normalized to the housekeeping gene Hprt1 then compared with noninjected control organs) in indicated organs from db/db mice injected with AAV9-cBIN1-V5. SKM, skeletal muscle; Pan, pancreas; K, kidney; Sp, spleen; Adi, adipose tissue; n = 4 animals per group. Data are presented as mean ± SEM. Unpaired 2-tailed Student’s t test or nonparametric Mann-Whitney U test was used for 2 group comparison. *, *** indicates P < 0.05, 0.001, respectively, for comparison versus db/m (C–F) or no virus controls (I). One-way ANOVA followed by Bonferroni’s test or nonparametric Kruskal-Wallis test followed by Dunn’s test was used for comparison between selected pairs (B–F). Two-way ANOVA followed by Tukey’s test was used for comparison on multiple timepoints among treatment groups (G and H). *, **, *** indicates P < 0.05, 0.01, and 0.001, respectively, for comparison versus db/m + GFP; † indicates P < 0.05 for comparison between db/db + GFP and db/db + cBIN1.