Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy

Abstract

Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as "diabetic cardiomyopathy". However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.

Keywords: cardiomyopathy; diabetes; diabetic cardiovascular complications; endothelium; heart failure; metabolism; vascular.

Fig. 1

Normal endothelial cell metabolism. In healthy endothelial cells, glucose enters the cell through the GLUT-1 receptor, in an insulin independent manner. Energy production occurs mostly by glycolysis, rather than through oxidative phosphorylation. During normal endothelial function, some of the glucose-6-phosphate that is produced during glycolysis gets shunted into the pentose phosphate pathway. The purpose of this pathway is to produce NADPH, an important antioxidant in endothelial cells, as well as pentoses, which can be used to produce nucleic acids, nucleotides, and amino acids. It also allows the conversion of glutathione disulfide (GSSG) back to glutathione (GSH), which helps to prevent oxidative stress by converting H₂O₂ to H₂O

Fig. 2

Hyperglycemia-induced metabolic derangement in endothelial cells. During diabetes, entry of glucose-6-phosphate into the pentose phosphate pathway is inhibited. This causes a reduction in the production of NADPH and a buildup of H₂O₂, which both contribute to oxidative stress in diabetic endothelial cells

Fig. 3

Effect of diabetic endothelial dysfunction on vasodilators and vasoconstrictors. Hyperglycemia in diabetes decreases vasodilation through the decreased bioavailability of nitric oxide (NO) and prostacyclin (PGI₂). It also caused an increase in endothelium-derived contracting factors including prostanoids, endothelin-1 (ET-1), angiotensin-II (Ang-II), dinucleotide uridine adenosine tetraphosphate (UP₄A), ROS, and cyclooxygenase (COX)-derived prostanoids. EC endothelial cell, SMC smooth muscle cell

Fig. 4

Mechanism of eNOS uncoupling. During diabetes, hyperglycemia activates NAD(P)H oxidase (NOX), which is responsible for converting oxygen into the superoxide anion (O₂^-), using up NADPH during the reaction. Superoxide reacts with NO to form peroxynitrite (ONOO^-). Peroxynitrite is believed to be the main cause of eNOS uncoupling in endothelial cells. Under normal physiological conditions, NO is synthesized by eNOS from L-arginine and oxygen, using BH₄ as a cofactor. During eNOS uncoupling, however, eNOS produces superoxide instead of NO, leading to oxidative stress in endothelial cells. It is thought that peroxynitrite reacts with BH₄, and that this loss of BH₄ is the main mechanism by which eNOS becomes uncoupled. However, more recent evidence suggests that other mechanisms may be involved

Fig. 5

Effects of mitochondrial oxidative stress on endothelial function. During diabetes, there is an increase in mitochondrial oxidative stress, which causes mitochondrial DNA damage. This activates the PARP-1 pathway in the nucleus of endothelial cells, which has been implicated in response to DNA injury. Activation of PARP-1 has been shown to inhibit Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), a key enzyme involved in glycolysis. This inhibition causes the buildup of glycolytic intermediates, which get shunted into the polyol pathway, the hexosamine biosynthesis pathway, or the glycation pathway. These pathways all contribute to endothelial dysfunction. Blue color represents nucleus and green represents the mitochondria