Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Department of Biology, Georgia State University, Atlanta, Georgia.
J Cell Physiol. 2019 Aug;234(8):13557-13570. doi: 10.1002/jcp.28034. Epub 2019 Jan 19.
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.
慢性高血糖及其并发症的流行给全球经济和全球医疗保健系统带来了巨大负担，这是一个亟待解决的问题。越来越多的证据表明，氧化应激和缺氧是高血糖的两个显著特征，它们共同起着关键作用，介导细胞凋亡。然而，其潜在的详细分子机制仍不清楚。我们观察到胰岛素样生长因子 (IGF1)-结合蛋白 3 (IGFBP3) 可以通过增加氧化应激来介导肾细胞中高糖诱导的细胞凋亡，基于这一观察结果，我们希望在本研究中了解这种情况是否也适用于心肌细胞，如果是这样，我们还想找到其相关的分子关键参与者，从而剖析潜在的分子途径。具体来说，我们使用了三种不同的细胞来源（H9c2 细胞、糖尿病大鼠和新生大鼠心室心肌细胞）作为我们的研究模型系统。我们使用了 Co-IP 测定和 Western blot 分析，并结合功能丧失推理、功能获得逻辑和抑制剂处理作为我们的主要分析工具。简而言之，我们的主要发现是高血糖可以诱导心肌 IGFBP3 的过度表达和分泌，高水平的 IGFBP3 可以将 IGF1 从 IGF1 存活途径中隔离出来，导致细胞凋亡，并且 IGFBP3 基因的上调依赖于低氧诱导因子 (HIF)1α 和活性氧。将这些发现放在一起，使我们能够提出改进的分子调控机制。总之，我们已经确定了 IGFBP3、HIF1 和脯氨酰羟化酶结构域在高血糖下连接氧化应激与缺氧以及细胞凋亡中的分子作用。
