{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:21:34Z","timestamp":1790068894137,"version":"4.0.1"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,1,19]],"date-time":"2019-01-19T00:00:00Z","timestamp":1547856000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,1,19]],"date-time":"2019-01-19T00:00:00Z","timestamp":1547856000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"Ministry of Science and Technology (formerly called National Science Council), Taiwan","award":["MOST 103-2320-B-039-007-MY3"],"award-info":[{"award-number":["MOST 103-2320-B-039-007-MY3"]}]},{"name":"China Medical University, Taichung, Taiwan","award":["DMR-107-130"],"award-info":[{"award-number":["DMR-107-130"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The prevalence of chronic hyperglycemia and its complications, imposing a critical burden on the worldwide economy and the global healthcare system, is a pressing issue. Mounting evidence indicates that oxidative stress and hypoxia, two noticeable features of hyperglycemia, play a joint crucial role in mediating cellular apoptosis. However, the underlying detailed molecular mechanism remains elusive. Triggered by the observation that insulin\u2010like growth factor (IGF1)\u2010binding protein 3 (IGFBP3) can mediate, in renal cells, high\u2010glucose\u2010induced apoptosis by elevating oxidative stress, we wish to, in this study, know whether or not the similar scenario holds in cardiac cells and, if so, to find its relevant molecular key players, thereby dissecting the underlying molecular pathway. Specifically, we used a combination of three different cellular sources (H9c2 cells, diabetic rats, and neonatal rat ventricular cardiomyocytes) as our model systems of study. We made use of Co\u2010IP assay and western blot analysis in conjunction with loss\u2010of\u2010function reasoning, gain\u2010of\u2010function logic, and inhibitor treatment as our main analytical tools. As a result, briefly, our main findings are that hyperglycemia can induce cardiac IGFBP3 overexpression and secretion, that high levels of IGFBP3 can sequester IGF1 from IGF1 survival pathway, leading to apoptosis, and that IGFBP3 gene upregulation is hypoxia\u2010inducible factor (HIF)1\u03b1\u2010dependent and reactive oxygen species dependent. Piecing these findings together allows us to propose the improved molecular regulatory mechanism. In conclusion, we have established the molecular roles of IGFBP3, HIF1, and prolyl hydroxylase domain in connecting oxidative stress with hypoxia and in cellular apoptosis under hyperglycemia.<\/jats:p>","DOI":"10.1002\/jcp.28034","type":"journal-article","created":{"date-parts":[[2019,1,19]],"date-time":"2019-01-19T14:43:45Z","timestamp":1547909025000},"page":"13557-13570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["ROS\u2010 and HIF1\u03b1\u2010dependent IGFBP3 upregulation blocks IGF1 survival signaling and thereby mediates high\u2010glucose\u2010induced cardiomyocyte apoptosis"],"prefix":"10.1002","volume":"234","author":[{"given":"Yao\u2010Te","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biological Science and Technology China Medical University Taichung 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