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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)1\u03b1 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 HIF1\u03b1 and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca<jats:sup>2+<\/jats:sup>, 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 HIF1\u03b1 and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.<\/jats:p>","DOI":"10.1038\/s42003-021-01676-3","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T11:05:04Z","timestamp":1613127904000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Amylin deposition activates HIF1\u03b1 and 6-phosphofructo-2-kinase\/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2095-7769","authenticated-orcid":false,"given":"Miao","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-7795","authenticated-orcid":false,"given":"Nan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3657-2978","authenticated-orcid":false,"given":"Chun","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7964-4260","authenticated-orcid":false,"given":"Yilin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-9374","authenticated-orcid":false,"given":"Lijie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0368-9398","authenticated-orcid":false,"given":"Liangbiao George","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"1676_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0140-6","volume":"13","author":"J Cantley","year":"2015","unstructured":"Cantley, J. & Ashcroft, F. 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