ROS‐ and HIF1α‐dependent IGFBP3 upregulation blocks IGF1 survival signaling and thereby mediates high‐glucose‐induced cardiomyocyte apoptosis

• Published in: Journal of cellular physiology Vol. 234; no. 8; pp. 13557 - 13570
• Main Authors: Huang, Yao‐Te, Liu, Chung‐Hung, Yang, Yao‐Chih, Aneja, Ritu, Wen, Su‐Ying, Huang, Chih‐Yang, Kuo, Wei‐Wen
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-08-2019
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Cardiomyocytes; Cell Line; Cell Survival - physiology; Diabetes mellitus; diabetic cardiomyopathy; Global health; Glucose; Growth factors; Heart; HIF1α; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Hyperglycemia - pathology; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Insulin; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor-binding protein 3; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neonates; Oxidative stress; PHD; PI3K/Akt; Prolyl hydroxylase; Proteins; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Regulatory mechanisms (biology); Secretion; Signal Transduction; Survival; Up-Regulation; Ventricle; hyperglycemia; hypoxia; diabetic cardiomyopathy; HIF1α; PHD; PI3K/Akt
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28034

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‐like growth factor (IGF1)‐binding protein 3 (IGFBP3) can mediate, in renal cells, high‐glucose‐induced 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‐IP assay and western blot analysis in conjunction with loss‐of‐function reasoning, gain‐of‐function 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‐inducible factor (HIF)1α‐dependent 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.
In this study, we utilize, mainly, H9c2 cells in conjunction with diabetic rats and neonatal rat ventricular cardiomyocytes (NRVMs), in some cases, as our model systems of study. Our aim in this study is to establish the molecular roles of insulin‐like growth factor‐binding protein 3 (IGFBP3), hypoxia‐inducible factor 1 (HIF1), and prolyl hydroxylase domain (PHD) in connecting oxidative stress with hypoxia and in cellular apoptosis under hyperglycemia.