Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes

Abstract

Aims The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes. Methods and results Hyperglycaemia induces increased nuclear factor-κB (NF-κB) signalling, up-regulation of miR-27a-3p, down-regulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signalling, down-regulation 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 signalling, down-regulating miR-27a-3p, up-regulating NRF2 expression, reducing TGF-β signalling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin-induced diabetic mice, whereas insulin alone does not improve cardiac function. Conclusions Our data indicate that disruption of hyperglycaemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signalling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory.

MRI study of cerebroprotective effects of renal denervation in patients with resistant hypertension and type 2 diabetes mellitus

“…В данном контексте сохранение негативного воздействия гипергликемии могло ограничивать протективное влияние РДН в отношении тканей головного мозга. Более того, формирование под влиянием длительно существующей гипергликемии «метаболической памяти» может запускать эффект «домино» в виде прогрессирующего сосудистого повреждения и периваскулярного фиброза [18]. Именно этим феноменом во многом объясняют сохранение высокого риска сердечно-сосудистых осложнений даже при достижении удовлетворительного гликемического контроля.…”

Endothelial Dysfunction and Diabetic Cardiomyopathy

“…These agents mainly function by modifying the properties of cardiac myofilament, rather than altering cytosolic Ca 2+ transients, thus leading to different modulation effects on myocardial relaxation and diastolic tone ( 112 ). Yao et al ( 113 ). demonstrated in endothelial cells hyperglycemia induces a series of changes, which are all memorized by endothelial cells and not erased when switched to a low glucose condition, leading to perivascular fibrosis and cardiac dysfunction.…”

“…Moreover, the production of NO, generation of ROS, and the mitochondrial oxygen consumption rate are found similar to the metabolic memory in endothelial cells. In vivo , the disruption of endothelial cell metabolic memory restores cardiovascular function by regulating corresponding signaling pathways in diabetic mice, whereas insulin alone does not improve cardiac function ( 113 ). This regulation on cardiac myocyte function by paracrine of endothelial cells is worth investigating both physiologically and in pathological states ( 112 ).…”

The Scope of HbA1c Variability and Risk of Vascular Complications Among Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Prospective Studies

“…The accurate mechanisms underlying HbA1c variability-related vascular diseases remain to be illuminated. Several assumptive mechanisms include the release of inflammation [38], oxidative stress [39], impaired endothelial function [40], insulin resistance [41], and metabolic memory [42]. Furthermore, some studies have suggested that HbA1c variability is related to other adverse risk factors, including unhealthy lifestyle behavior (poor diet) [43], irregular compliance to therapy, and multimorbidity [44].…”