Endothelial Cell Metabolic Memory Causes Cardiovascular Dysfunction In Diabetes.

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.