Advanced glycation endproduct (AGE) accumulation  and AGE receptor (RAGE) up-regulation contribute  to the onset of diabetic cardiomyopathy.
Diabetic cardiomyopathy is manifested by compromised systolic and diastolic function. This study was designed to examine the role of advanced glycation endproduct (AGE) and AGE receptor (RAGE) in diabetic cardiomyopathy. Heart function was assessed in isolated control and streptozotocin-induced diabetic hearts following in vivo RAGE gene knockdown using RNA interference. Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR(90)). RAGE was assayed by RT-PCR and immunoblot. Diabetes significantly enhanced cardiac MG, AGE and RAGE levels accompanied with colocalization of AGE and RAGE in cardiomyocytes. Diabetes-elicited increase in RAGE was inhibited by in vivo siRNA interference. The AGE formation inhibitor benfotiamine significantly attenuated diabetes-induced elevation in MG, AGE, RAGE and collagen cross-linking without affecting hypertriglyceridaemia and hypercholesterolaemia in diabetes. Diabetes markedly decreased LV contractility, as evidenced by reduced +/-dP/dt and LV developed pressure (LVDP), which were protected by RAGE gene knockdown. In addition, MG-derived AGE (MG-AGE) up-regulated cardiac RAGE mRNA and triggered cardiomyocyte contractile dysfunction reminiscent of diabetic cardiomyopathy. The MG-AGE-elicited prolongation of TPS and TR(90) was ablated by an anti-RAGE antibody in cardiomyocytes. Interestingly, MG-AGE-induced cardiomyocyte dysfunction was associated with mitochondrial membrane potential (MMP) depolarization and reduced GSK-3beta inactivation in control cardiomyocytes, similar to those from in vivo diabetes. Treatment with siRNA-RAGE ablated diabetes-induced MMP depolarization and GSK-3beta inactivation. Collectively, our result implicated a role of AGE-RAGE in the pathogenesis of diabetic cardiomyopathy.
Ma
Heng
H
Department of Physiology, Fourth Military Medical University, Xi'an, China.|Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Li
Shi-Yan
SY
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Xu
Peisheng
P
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Babcock
Sara A
SA
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Dolence
E Kurt
EK
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Brownlee
Michael
M
Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA.
Li
Ji
J
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Ren
Jun
J
Department of Physiology, Fourth Military Medical University, Xi'an, China.|Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008297:Male; D051379:Mice; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin; D015854:Up-Regulation
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013311:Streptozocin