Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.
Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.
复制标题
DOI：
10.1093/cvr/cvab013
复制
发表时间：
2021-01
影响因子：
10.8
通讯作者：
Yufeng Yao;Qixue Song;Changqing Hu;Xingwen Da;Yubing Yu;Zuhan He;Chengqi Xu;Qiuyun Chen;Q. Wang
中科院分区：
文献类型：
--
作者：
Yufeng Yao;Qixue Song;Changqing Hu;Xingwen Da;Yubing Yu;Zuhan He;Chengqi Xu;Qiuyun Chen;Q. Wang
目的本研究的目的是确定高血糖诱导的内皮细胞代谢记忆的分子机制，并表明其在糖尿病心血管功能障碍发展中的重要意义。方法与结果高血糖诱导核因子-κB （NF-κB）信号转导升高，miR-27a-3p上调，核因子-红细胞2相关因子2 （NRF2）表达下调，转化生长因子-β (TGF-β)信号转导升高，miR-29下调，诱导内皮细胞向间质转化（EndMT），这些都被ECs记忆，当切换到低糖状态时不会被清除，从而导致血管周围纤维化和心功能障碍。在两种不同类型的ec中，相似的代谢记忆效应在一氧化氮（NO）的产生、活性氧（ROS）的产生和线粒体耗氧率方面被发现。在ECs中观察到的代谢记忆效应被NRF2激活剂叔丁基对苯二酚和miR-27a-3p抑制剂阻断。在体内，在链脲佐菌（STZ）诱导的糖尿病小鼠胰岛素治疗过程中，NRF2激活剂和miR-27a-3p抑制剂通过降低NF-κB信号、下调miR-27a-3p、上调NRF2表达、降低TGF-β信号、抑制EndMT，阻断心脏血管周围纤维化，恢复心血管功能，而单独使用胰岛素并不能改善心功能。结论：我们的数据表明，在糖尿病治疗过程中，高血糖诱导的EC代谢记忆的破坏是恢复心功能所必需的，并确定了NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT参与代谢记忆的新分子信号通路。关于高血糖（hyperglycemia）是否会诱导代谢记忆，从而导致糖尿病患者长期的破坏性心血管并发症，存在争议。在这里，我们证明了高血糖诱导的内皮细胞代谢记忆导致小鼠糖尿病心脏血管周围纤维化和心功能障碍，并确定了NF-kB/miR-27a-3p/NRF2/ROS/TGF-β-EndMT是其信号机制。我们发现，通过胰岛素治疗糖尿病，需要NRF2激活剂或miR-27a-3p抑制剂破坏代谢记忆才能实现对心功能障碍的治疗效果。因此，抑制代谢记忆是一种新的策略，可以更好地预防心血管并发症，改善糖尿病患者的临床预后。
AIMS The aim of this study was to identify the molecular mechanism for hyperglycemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes. METHODS AND RESULTS Hyperglycemia induces increased nuclear factor-κB (NF-κB) signaling, upregulation of miR-27a-3p, downregulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signaling, downregulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signaling, downregulating miR-27a-3p, upregulating NRF2 expression, reducing TGF-β signaling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin (STZ)-induced diabetic mice, whereas insulin alone does not improve cardiac function. CONCLUSIONS Our data indicate that disruption of hyperglycemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signaling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory. TRANSLATIONAL PERSPECTIVE Controversy exists on whether high blood glucose (hyperglycemia) induces metabolic memory that may cause long-lasting damaging cardiovascular complications in diabetic patients. Here, we demonstrate that hyperglycemia-induced metabolic memory in endothelial cells causes cardiac perivascular fibrosis and cardiac dysfunction in diabetes in mice, and identify NF-kB/miR-27a-3p/NRF2/ROS/TGF-β-EndMT as the signaling mechanism. We show that disruption of metabolic memory by a NRF2 activator or miR-27a-3p inhibitor is required to achieve therapeutic effect on cardiac dysfunction by insulin treatment of diabetes. Thus, inhibition of metabolic memory is a novel strategy to better prevent cardiovascular complications and improve the clinical outcome of diabetic patients.