Amylin deposition activates HIF1\u03b1 and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates

Lijie Wu,Nan Li,Chun Qu,Miao Liu,Yilin Gao,Liangbiao George Hu

doi:10.1038/s42003-021-01676-3

Abstract

Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.

Highlights

Type-2 diabetes (T2D) is a chronic metabolic disorder characterized by a progressive defect in insulin secretion from pancreatic β-cells
Amylin in Non-human primates (NHPs) possesses an amyloidogenic region, similar to that observed in humans[17]; the role of amylin in NHP hearts warrants further investigation
We first observed that NHPs with heart failure (HF) have amylin deposition in cardiomyocytes (Fig. 2)

Summary

Introduction

Type-2 diabetes (T2D) is a chronic metabolic disorder characterized by a progressive defect in insulin secretion from pancreatic β-cells. Non-human primates (NHPs), dogs and cats, but not of rodents (mice and rats), possesses an amyloidogenic promoting region and can form toxic aggregates when overexpressed[12,13,14,15,16,17] These small membrane-permeable amylin oligomers cause oxidative[18,19] and inflammatory stress[20,21], contributing to apoptosis in the pancreas[13,22]. Uncoupling between glucose uptake and oxidation is observed in HF, resulting in an increase in glycolysis and conversion of pyruvate to lactate[36] These changes contribute to cardiomyocyte dysfunction[9,37,40].

Objectives

Methods

Results

Conclusion