Abstract 13900: Hyperamylinemia Exacerbates Sarcolemmal Lipid Peroxidation in Diabetic Hearts
Background: Chronic hypersecretion of the pancreatic hormone amylin leads to infiltration of oligomeric amylin in cellular membranes, which contributes to β-cell dysfunction and type-2 diabetes (T2D). We recently showed that oligomeric amylin also accumulates in myocardium of patients with obesity or T2D.
Hypothesis: Oligomeric amylin may infiltrate the sarcolemma exposing membrane lipids to peroxidation by ROS, thus exacerbating myocardial oxidative stress.
Methods: We investigated the relationship between incorporated amylin and lipid peroxidation in ventricular myocytes from obese patients (BMI≥30) with heart failure (HF) (O-HF group; N=6), obese humans without HF (O-NF group; N=6) and healthy people with BMI<30 (L-NF group; N=4). The proposed mechanism was also tested in an animal model of myocardial amylin accumulation (HIP rat) and control rat myocytes incubated with oligomeric amylin.
Results: Compared to L-NF controls, the myocyte level of amylin is increased in both O-HF group (10-fold; P<0.01) and O-NF group (3.5-fold; P<0.05). Western blot analysis of 4-HNE, an aldehydic product of lipid peroxidation, showed that this marker is also increased in the O-NF group (4-fold; P<0.01) and even further in O-HF group (6-fold; P<0.001). Confocal microscopy with fluorescent probes of lipid peroxidation C11-BODIPY and Liperfluo indicates increased lipid peroxidation in HIP rat myocytes (2-fold; P<0.001). Significantly lower levels of lipid peroxide were found in age- and glucose-matched UCD rats which do not accumulate amylin in the heart. Moreover, incubation of control rat myocytes with exogenous amylin oligomers (50 μM; 2 hours) increases lipid peroxidation and ROS production. In contrast, incubation for the same duration with 400 mg/dl glucose had no effect on the lipid peroxidation level. Reducing ROS in vitro, by pre-incubation with 5mM NAC, or amylin oligomer-mediated sarcolemmal damage, by 50 μM membrane sealant P188, mitigates lipid peroxidation.
Conclusions: Together, these findings support the hypothesis that circulating oligomeric amylin infiltrates cardiac myocytes in humans and exacerbates lipid peroxidation. Strategies to mitigate myocardial deposition of amylin should be pursued.
Author Disclosures: M. Liu: None. X. Peng: None. S. Despa: None. K. Margulies: None. F. Despa: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.