Abstract 1371: Markers and Mediators of Autophagy Are Increased in the Hearts of Two Murine Models of Type 2 Diabetes Irrespective of Cardiac Function
The excess supply of fuels to the diabetic heart results in dysfunctional mitochondria and oxidized proteins. Autophagy, a pathway for lysosomal degradation of organelles and proteins, has been shown to eliminate damaged cellular components. We proposed that autophagy is increased in the hearts of Type 2 diabetics. To test this hypothesis, we used two murine models of the disease: the db/db mouse and the NONcNZO10/LtJ (RCS10) mouse. Although previous reports have demonstrated insulin resistance and increased triglyceride levels in the RCS10 heart, contractile function had not been examined. Cardiac function of the RCS10 mice and SWR/J controls (n=4 for each group) was evaluated via echocardiography at 15 weeks and 8 months. While left ventricular mass was significantly increased at both time points in the RCS10 mice (p<0.05), there were no significant differences in fractional shortening or left ventricular end systolic or diastolic diameters. In contrast, other investigators have shown that db/db mice exhibit both systolic and diastolic dysfunction in the absence of cardiac hypertrophy. Using these two models, we were able to examine autophagy in diabetic hearts with preserved and impaired cardiac function. Protein levels of specific autophagosomal marker LC3-II and mediators of autophagy Beclin1 and Atg5–12 conjugate were significantly increased in 15-week-old RCS10 mice who had been hyperglycemic (non-fasting blood glucose >250mg/dl) for at least 3 weeks compared to SWR/J controls (p<0.05, n=5 for each group). Hearts from age-matched db/db mice had significantly increased protein levels of LC3-II, Beclin1, Atg5–12 conjugate, and Atg10 compared to C57BLKS controls (p<0.05, n=10 for each group). Protein carbonylation was increased in the db/db mice (p<0.05). Interestingly, there was a 66% decrease in SOD2 transcripts and a 53% decrease in GPX1 transcripts in RCS10 hearts compared to controls (p<0.05, n=4 for each group). In conclusion, our results suggest that autophagy is increased in the diabetic heart regardless of the functional status of the myocardium.