Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel.
Biomedical Core Facility, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Cardiovasc Res. 2017 Feb;113(2):134-146. doi: 10.1093/cvr/cvw228. Epub 2016 Nov 7.
Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model.
We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance.
Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis.
肥胖和 2 型糖尿病（T2D）引发一种有害的应激诱导性心脏重构过程，即心肌病。这些疾病在西方世界是一个严重且普遍的健康问题，但潜在的分子基础尚不清楚。ATF3 是一种“早期即刻”基因，其表达在多种应激源（如代谢、氧化、内质网和炎症）作用下高度且短暂地被诱导，这些应激源与 T2D 心肌病有关。ATF3 在糖尿病性心肌病中的作用尚不清楚。我们的研究旨在研究 ATF3 表达对肥胖诱导的 T2D 小鼠模型中心肌细胞、心脏功能和葡萄糖稳态的影响。
我们使用野生型（WT）小鼠以及心脏特异性 ATF3 缺陷（ATF3-cKO）的突变型小鼠。小鼠喂食高脂肪饮食（HFD）15 周。HFD 诱导心肌细胞中 ATF3 的高表达。检查小鼠的心脏重构过程并评估糖尿病状态。与 WT 小鼠相比，HFD 喂养的 ATF3-cKO 小鼠表现出严重的心肌纤维化、更高的心脏肥大标志物水平、增加的炎症和更差的心脏功能。有趣的是，与 HFD 喂养的 WT 小鼠相比，HFD 喂养的 ATF3-cKO 小鼠表现出更高的高血糖和葡萄糖耐量降低，尽管血液胰岛素水平升高。升高的心脏炎性细胞因子 IL-6 和 TNFα 导致胰岛素信号受损，可能部分解释了外周葡萄糖耐量降低。
心脏 ATF3 在抑制 HFD 诱导的心脏重构过程中具有保护作用。ATF3 发挥与 T2D 诱导性心肌病相关的局部和全身作用。这项研究提供了心脏重构过程与血糖稳态之间的紧密关系。
