Department of Translational Safety and Bioanalytical Sciences, Amgen R&D (Shanghai) Co. Ltd., Shanghai, China.
Commun Biol. 2021 Feb 12;4(1):188. doi: 10.1038/s42003-021-01676-3.
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 Ca, 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.
高胰岛淀粉样肽血症可诱导胰岛淀粉样肽聚集和毒性，从而导致 2 型糖尿病（T2D）的发生。研究发现，肥胖和 T2D 患者心脏中的胰岛淀粉样肽沉积会加速心脏功能障碍。非人类灵长类动物（NHP）与人类具有相似的遗传、代谢和心血管过程。然而，NHP 中心脏胰岛淀粉样肽的潜在机制，特别是与缺氧诱导因子（HIF）1α 和 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3（PFKFB3）信号通路相关的机制尚不清楚。在这里，我们证明在 NHP 中，心力衰竭（HF）中的胰岛淀粉样肽沉积通过激活 HIF1α 和 PFKFB3 信号通路导致心脏功能障碍。这在两种体外心肌细胞模型中得到了证实。此外，在胰岛淀粉样肽处理的细胞中观察到细胞内 Ca、活性氧、线粒体功能和乳酸水平的改变。我们的研究表明，胰岛淀粉样肽在 HF 的 NHP 中激活 HIF1α 和 PFKFB3 信号通路中具有病理作用，将胰岛淀粉样肽确立为心脏病患者的一个有前途的治疗靶点。
