Abstract Body (Do not enter title and authors here): Introduction/ Background
Patients with diabetic heart failure (HF) present myocardial accumulation of amylin, an amyloid-forming peptide hormone that is synthesized and co-secreted with insulin. Amylin deposits are commonly detected in the coronary microvasculature.
Research Questions/ Hypothesis
Amylin deposition in the coronary microvasculature impairs myocyte energy metabolism by activation of hypoxia signaling.
Goals/ Aims
We investigated the potential role of pancreatic amylin dysregulation in myocardial hypoxia-inducible factor (HIF) activation and metabolic remodeling.
Methods/ Approach
We used transgenic rats that express amyloidogenic human amylin under regulation of the insulin II promoter (HIP rats) and develop amylin-pathology related type-2 diabetes. Wild-type (WT) littermates that express rat amylin (non-amyloidogenic) served as non-diabetic controls.
Results/ data (descriptive and inferential statistics)
Histological analyses of heart sections show amylin deposits in the coronary microvasculature, microhemorrhages and lower capillary density in hearts from HIP vs. WT rats. Expression of both HIF-1α and HIF-2α is elevated in diabetic HIP rat hearts compared to age-matched WT controls (by 54% and 56%). Analysis of differentially expressed genes in hearts from HIP vs. WT rats shows upregulation of pyruvate dehydrogenase kinase and downregulation of pyruvate dehydrogenase phosphatase. These changes suggest that activity of pyruvate dehydrogenase is reduced and therefore less pyruvate is converted to acetyl-CoA to enter the Krebs cycle in HIP rat hearts. In line with a metabolic switch from oxidative phosphorylation to anaerobic glycolysis, our metabolomics data show elevated myocardial levels of glucose-6-phosphate, fructose-6-phosphate and pyruvate in hearts from HIP vs. WT rats. Mitochondrial Ca²⁺ concentration is decreased in cardiac myoytes from diabetic HIP rats vs. WT controls, which is known to limit ATP production and to cause oxidative stress by slowing the regeneration of NADH and NADPH. In agreement with this mechanism, HIP rat myocytes show oxidative stress that is mitigated by the mitochondrial ROS scavenger MitoTempo, and lower ATP levels compared to WT hearts (0.84±0.10 vs. 1.25±0.14 pmol/mg protein).
Conclusions
Pancreatic hypersecretion of amyloid-forming amylin in prediabetes results in hypoxic-ischemic myocardial injury, leading to impairment of myocyte energy metabolism.