Abstract 16963: Pre-Diabetes Promotes Buildup of Amylin in the Heart That Alters Cardiac Function by Remodeling the Myocytes
Hyperamylinemia and consequent amylin oligomerization are key components of the metabolic syndrome. Their effects on cardiac function remain largely unknown. We recently found amylin deposits in failing hearts from obese and diabetic patients, but not in non-failing hearts or in failing hearts from lean, non-diabetic individuals. Using rats that express amyloidogenic human amylin in the pancreas (HIP rats) as a model of hyperamylinemia, we found that cardiac amylin accumulation increases sarcolemmal Ca2+ leak, Ca2+ transients, and diastolic [Ca2+]i even in pre-diabetic insulin resistance. Elevated [Ca2+]i may activate the Ca2+-dependent CaMKII-HDAC and calcineurin-NFAT hypertrophic signaling. We investigated this hypothesis by assessing the nuclear vs. cytosolic localization of HDAC4 and NFATc4 by immunofluorescence. We found a lower nuclear-to-cytosolic HDAC4 ratio in myocytes from HIP vs. littermate controls (1.10±0.04 vs. 1.38±0.03), indicating nuclear export of HDAC. In contrast, the NFATc4 nuclear-to-cytosolic ratio was elevated in HIP rats (1.94±0.05 vs. 1.76±0.04), suggesting the nuclear import of NFAT. Activation of CaMKII-HDAC and calcineurin-NFAT signaling pathways was correlated with overexpression of brain natriuretic peptide (BNP) by 100±30% and SERCA downregulation (by 20±4%). Phospholamban and Na+/Ca2+ exchanger remained unaltered. These results suggest that amylin activates Ca2+-dependent transcriptional signaling leading to SERCA remodeling and BNP-mediated hormonal alterations. Next we incubated isolated rat myocytes with 50µM human amylin for 2h, which led to amylin oligomerization and attachment to the sarcolemma, elevated Ca2+ transients (by 95±5%), and increased nuclear-to-cytosolic ratio of NFATc4 (from 1.71±0.05 to 1.94±0.07). HDAC4 localization was not altered by this acute amylin exposure. Amylin oligomerization, attachment to sarcolemma, and consequent Ca2+ dysregulation were prevented by co-incubation with the proteolytic molecule human plasmin and 14,15-epoxyeicosatrienoic acid (EET). We conclude that amylin accumulation accelerates cardiac hypertrophy and remodeling in diabetes and increasing the level of endogenous EETs may reduce the cardiotoxicity of hyperamylinemia.
- © 2012 by American Heart Association, Inc.