Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.

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.

• Authors: Miao Liu, Nan Li, Chun Qu, Yilin Gao, Lijie Wu, Liangbiao George Hu
• Journal: Communications biology (Commun Biol) Vol. 4 Issue 1 Pg. 188 (02 12 2021) ISSN: 2399-3642 [Electronic] England
• PMID: 33580152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Islet Amyloid Polypeptide
• Reactive Oxygen Species
• Phosphofructokinase-2

Topics

• Animals
• Apoptosis
• Calcium Signaling
• Cells, Cultured
• Disease Models, Animal
• Female
• Heart Failure (enzymology, pathology, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Islet Amyloid Polypeptide (metabolism)
• Macaca fascicularis
• Male
• Mitochondria, Heart (enzymology, pathology)
• Myocardium (enzymology, pathology)
• Myocytes, Cardiac (enzymology, pathology)
• Phosphofructokinase-2 (metabolism)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Stroke Volume
• Ventricular Function, Left
• Ventricular Pressure
• Rats