New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis

Abstract

Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed.

Keywords: Atherosclerosis; Diabetes mellitus; Gut microbiota; MicroRNA; Reactive oxygen species.

Fig. 1

Four hyperglycemia-induced pathogenic pathways which are related to overproduction of ROS and inflammation progression in atherosclerosis. Hyperglycemia causes mitochondrial overproduction of ROS via a greater oxygen use, high redox potential and mito-fission state. Increased ROS leads to nuclear DNA damage and activates nuclear PARP, which inhibits GAPDH activity, shunting early glycolytic intermediates into pathogenic signaling pathways, including activation of polyol pathway, PKC and AGE. These pathways amplify production of ROS and promote pathogenic inflammation progression in atherosclerosis. The polyol pathway generates ROS by consuming NADPH and GSH, and increasing subsequent NADH oxidation during the conversion of sorbitol to fructose. As a key rate-limiting enzyme of polyol pathway, AR promotes the expression of inflammatory cytokines such as TNF-α and NF-κB. Inhibition of GAPDH contributes to DHAP production and subsequent increase of PKC and AGE, both of which induce an increase in NADPH oxidase, inflammation factors expression and a decrease in eNOS activation. Moreover, PKC promotes insulin resistance by inhibiting downstream expression of PI3K-AKT. As a precursor of the majority of AGE adducts, methylglyoxal is increased in hyperglycemia, and then promote the expression of AGE, RAGE and RAGE ligands.

Fig. 2

Downstream products of ROS promote endothelial cells (ECs) dysfunction in atherosclerosis. Ox-LDL induces ECs apoptosis via caspase dependent or independent pathway, and induces ECs autophage by repressing the Rheb-mediated mTOR/P70S6kinase/4EBP signaling pathway through increased miR-155 expression. Furthermore, ox-LDL induces oxidative stress in ECs through agumented NADPH oxidase and uncoupled eNOS. ERK5 SUMOylation induced by ROS leads to transrepression of atheroprotective genes PPARγ and KLF2/4-mediated eNOS expression, both of which increase NF-κB activation. Decreased adiponectin increase NF-κB activation, and decreased AMPK increase ER stress induced by ox-LDL via enhanced SERCA oxidation.

Fig. 3

Pathogenic mechanisms induced by ROS to promote foam cells formation. In diabetes mellitus, increased ROS induce ox-LDL production and augment of SR density, promoting the cholesterol accumulation in macrophage. Decreased adiponectin induced by ROS also promotes cholesterol accumulation via increased expression of ACAT-1 and SR. Downregulated AMPK improve cholesterol accumulation in macrophage through loss of phosphorylating ACC1 at Ser79 and ACC2 at Ser221. In macrophage, the activity of NF-κB is increased by reduced adiponectin through AdipoRX and by decreased AMPK upregulating SIRT1, FOXO and PGC-1α. Decreased AMPK also increases NLRP3 activation in macrophage, and promote expression of inflammatory factors. These all contribute to the foam cells formation in diabetes mellitus-accelerated atherosclerosis. ASC, apoptosis-associated speck-like protein containing CARD.

Fig. 4

Microflora dysfunction contributes to atherosclerosis progression. Diabetes mellitus induce microflora dysfunction and subsequent inflammation progression. LPS produced by excessive gram-negative bacteria can activate NF-κB via TLR-4-MyD88 to increase the expression of inflammatory factors such as IL-6 and TNF-α. And increased Helicobacter pylori (H. pylori) can also induce the expression of TNF-α and IL-6. Increase of Escherichia coli (E. coli) promotes the production of uric acid, which contributes to the overproduction of oxygen free radicals, causing vascular endothelial dysfunction. Increased choline induces TMAO generation, promoting macrophage CD36/SR-AI mRNA and protein expression, increasing macrophage foam cells formation. FMO3, flavin-containing monooxygenase 3.