Abstract 16285: Advanced Glycation End Products Disrupts Calcium Homeostasis Leading to ER Stress and Cardiac Contractile Dysfunction in Diabetes
Diabetes mellitus leads to accumulation of reactive oxygen species, oxidative stress and cardiac contratile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of advanced glycation endproducts (AGEs) and receptor for AGE (RAGE) in streptozotocin (STZ)-induced diabetic cardiac defect. Cardiac contractile function was assessed in normal FVB and STZ (200 mg/kg, 2 wks)-induced diabetic mice treated with or without aminoguanidine, an AGE inhibitor for 2 wks, using echocardiography and edge-detction techniques. Diabetes triggers AGE accumulation (135+/−18% of FVB group) and compromised cardiac contractile function shown as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening (by 25-40%), prolonged relengthening duration (by 29+/−7%) and impaired intracellular Ca2+ homeostasis, the effects of which were alleviated or ablated by aminoguanidine. Levels of RAGE was unaffected by either diabetes or aminoguanidine. Diabetes also inhibited sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity (28+/−6%) and increased ER stress, the effect of which was abrogated by aminoguanidine. In vitro study revealed that thapsigargin compromised murine cardiomyocyte mechanical function and ER stress in a manner similar to AGE while the two produced no additive effect. Transfection of SERCA2a adenovirus in rat neonatal cardiomyocytes resuced against AGEs incubation-induced oxidative stress (GSH/GSSH ratio), ER stress and intracellular Ca2+ mishandling (intracellular Ca2+ overload and prolonged Ca2+ clearance). Taken together, we established that accumulation of AGEs distuturbs calcium metablism, which led to ER stress and cardiac dysfunction in diabetes. This research is supported by Wyoming INBRE (P20RR016474).
- © 2011 by American Heart Association, Inc.