Abstract 14408: Hyperamylinemia Increases IL-1β Synthesis in the Heart via Peroxidative Sarcolemmal Injury
Introduction: Failing hearts of patients with obesity or type-2 diabetes contain large deposits of amylin, a diabetogenic hormone co-secreted with insulin.
Hypothesis: Amylin deposition destabilizes the sarcolemma leading to peroxidative sarcolemmal damage and inflammation.
Methods: The relationship of amylin deposition with the levels of 4-hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA) and cytokines (IL-1β, TNF-α, IL-6 and IL-10) were tested in myocardial tissue from patients with heart failure (HF) and obesity (BMI≥30; O-HF; N=7) or type-2 diabetes (D-HF; n=5) vs. organ donors with BMI<30 and no heart failure or diabetes (Ctl group; N=7). To further test the hypothesis, we used diabetic rats expressing human amylin in the pancreas (HIP rats; n=25), age- and glucose-matched diabetic rats expressing only non-amyloidogenic rat amylin (UCD rats; n=12), normal mice injected with aggregated human amylin (2 μg/g body weight; n=8) or saline (n=8), and in vitro cell models.
Results: Myocyte amylin uptake is associated with increased levels of 4-HNE, MDA and IL-1β. Compared to Ctl, amylin-MDA is 3.1-fold increased in O-HF (p<0.001) and 1.3 fold in D-HF (p<0.05). Amylin-4-NE adducts are increased 2.4 fold in O-HF (p<0.001) and 3.1-fold in D-HF (p<0.001). IL-1β is increased by 3.4-fold in O-HF (P<0.001) and by 1.2-fold in D-HF (P<0.05).. These pathological changes are mirrored in HIP rats and normal mice intravenously injected with aggregated amylin, but not in diabetic UCD rats. In addition, HIP rats show elevated TNF-α, but unchanged levels of IL-6 and IL-10. In isolated rat cardiac myocytes, aggregated amylin (50 μM; 2 h) destabilizes the sarcolemma and generates reactive aldehydes leading to increased synthesis of IL-1β (2.4-fold; P<0.001). In contrast, incubation for the same duration with 400 mg/dl glucose had no effect on lipid peroxidation and IL-1β synthesis. Blocking either myocyte amylin uptake (by surfactants), or the lipid peroxidation chain reaction (by NAC), demonstrated that peroxidative membrane injury is upstream of IL-1β increased synthesis.
Conclusion: These data suggest that exacerbated synthesis of IL-1β is a critical stress-activated signaling pathway in response to the interaction of aggregated amylin with myocytes.
Author Disclosures: M. Liu: None. N. Verma: None. S. Despa: None. K.B. Margulies: None. F. Despa: None.
- © 2016 by American Heart Association, Inc.