Abstract 16202: Endoplasmic Reticulum (ER) Stress is Critical for the Development of Diabetic Cardiomyopathy
Endoplasmic reticulum (ER) stress, resulting from failure of ER's capacity for protein folding, is considered to play an important role in the metabolic alterations of type 2 diabetes mellitus (DM). We hypothesized that ER stress in the heart is an essential pathogenetic component of diabetic cardiomyopathy. C57BL/6J mice were fed a high fat diet (HFD, 45% kcal fat) or normal diet (ND, 10% kcal fat) for 6 months. Compared to ND mice, HFD mice exhibited significant (p<0.01) obesity (body weight [BW] 47±4 vs 32±2 g), fasting hyperglycemia (blood glucose 205±32 vs 114±18 mg/dL), hyperinsulinemia (13.7±7.5 vs 1.5±0.5μg/L), and increased plasma non-esterified fatty acids indicative of type 2 DM. HFD hearts also exhibited (p<0.01): 1) increased posterior wall thickness (1.0±0.1 vs. 0.8±0.1 mm) and reduced LV chamber size (EDV 39±12 vs 53±15 μL) with preserved LVEF by echocardiography; 2) increased myocyte area (357±82 vs 209±37 μm2) and ANF expression; 3) augmented interstitial fibrosis (1.7±0.7 vs 0.6±0.3%); 4) increased inflammatory cytokine gene expression; and 5) increased expression of the ER chaperones Grp94, Grp78 and calreticulin. These changes occurred with increased diastolic LV chamber stiffness in the absence of hypertension, and were consistent with diabetic cardiomyopathy. HFD mice were then given taurine-conjugated ursodeoxycholic acid (TUDCA 500 mg/kg/d ip), a bile acid conjugate shown to improve ER protein folding capacity, or PBS (vehicle) for 4 wk. Compared to PBS, TUDCA markedly (p < 0.05) improved BW (36±4 vs 45±4 g) and metabolic abnormalities (blood glucose 133±12 vs 175±18 mg/dL; plasma insulin 5.7±3.8 vs 13.4±9.6 μg/L). Moreover, TUDCA normalized LV wall thickness (0.8±0.2 vs 0.94±0.2 mm), chamber size, and chamber stiffness and tended to improve myocyte insulin sensitivity measured by extracellular flux analysis of glucose utilization (177±26 vs 106±63%). We concluded that LV hypertrophy and diastolic dysfunction in type 2 DM is characterized by the activation of inflammation and ER stress in the heart, and that exogenous administration of the chemical chaperone TUDCA normalizes cardiac dysfunction. This suggests that chemical chaperones to reduce ER stress may be a viable treatment approach for diabetic cardiomyopathy in humans.
- © 2010 by American Heart Association, Inc.