Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy.
OBJECTIVE
Compelling epidemiological and clinical evidence has identified a specific cardiomyopathy in diabetes, characterized by early diastolic dysfunction and adverse structural remodeling. Activation of the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) promotes physiological cardiac growth and enhances contractile function. The aim of the present study was to examine whether cardiac-specific overexpression of IGF-1R prevents diabetes-induced myocardial remodeling and dysfunction associated with a murine model of diabetes.


METHODS
Type 1 diabetes was induced in 7-week-old male IGF-1R transgenic mice using streptozotocin and followed for 8 weeks. Diastolic and systolic function was assessed using Doppler and M-mode echocardiography, respectively, in addition to cardiac catheterization. Cardiac fibrosis and cardiomyocyte width, heart weight index, gene expression, Akt activity, and IGF-1R protein content were also assessed.


RESULTS
Nontransgenic (Ntg) diabetic mice had reduced initial (E)-to-second (A) blood flow velocity ratio (E:A ratio) and prolonged deceleration times on Doppler echocardiography compared with nondiabetic counterparts, indicative markers of diastolic dysfunction. Diabetes also increased cardiomyocyte width, collagen deposition, and prohypertrophic and profibrotic gene expression compared with Ntg nondiabetic littermates. Overexpression of the IGF-1R transgene markedly reduced collagen deposition, accompanied by a reduction in the incidence of diastolic dysfunction. Akt phosphorylation was elevated approximately 15-fold in IGF-1R nondiabetic mice compared with Ntg, and this was maintained in a setting of diabetes.


CONCLUSIONS
The current study suggests that cardiac overexpression of IGF-1R prevented diabetes-induced cardiac fibrosis and diastolic dysfunction. Targeting IGF-1R-Akt signaling may represent a therapeutic target for the treatment of diabetic cardiac disease.
Huynh
Karina
K
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia, and the Department of Medicine, Monash University, Melbourne, Victoria, Australia.
McMullen
Julie R
JR
Julius
Tracey L
TL
Tan
Joon Win
JW
Love
Jane E
JE
Cemerlang
Nelly
N
Kiriazis
Helen
H
Du
Xiao-Jun
XJ
Ritchie
Rebecca H
RH
D000818:Animals; D001783:Blood Flow Velocity; D006332:Cardiomegaly / Q000235:genetics; D009202:Cardiomyopathies / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000517:prevention & control*; D003971:Diastole; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D013599:Systole
D017526:Receptor, IGF Type 1