Soluble RAGEs and cardiovascular risk factors in adult offspring of patients with premature coronary heart disease

Figures

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  Figure 1. Advanced glycation end product (AGE) formation. The glycation reaction takes place by the modification of amino-terminal groups of proteins, phospholipids, or nucleic acids, by glucose or other monosaccharides leading to the generation of a Schiff Base and an Amadori product (early glycation). The auto-oxidation of glucose and rearrangements of the Schiff Base and the Amadori product, as well as the oxidation of amino acids, lipids or ketone bodies, and inflammation, promotes the generation of oxoaldehydes (such as glyoxal, methylglyoxal, and glycolaldehyde). They lead to the rapid and irreversible generation of AGEs, including heterogenous compounds, such as, pentosidine, argypirimidine, pyrraline, carboxymethyllysine, and carboxyethyllysine.

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  Figure 2. Intracellular formation of AGEs. During hyperglycemia, enhanced glucose flux through glycolysis induces the generation of superoxide anion by the mitochondria. Poly (ADP- ribose) polymerase (PARP) that protects DNA from cleavage induces a posttranslational modification of the glyceraldehyde 3P-dehydrogenase (GADPH) impairing glycolysis. Substrate (glyceraldehyde 3 phosphate and dihydroxyacetone phosphate) deviation leads to the generation of methylglyoxal that induces the formation of AGEs. Moreover, inflammation, fatty acid, amino acid, and ketone body oxidation generate oxoaldehydes, including glyoxal and glycolaldehyde that promote AGE generation. Oxidative stress increases by AGEs and by other biochemical pathways elicited by hyperglycemia (hexosamine, polyol, and protein kinase C). This vicious circle feeds the formation of AGEs and oxidative stress that is the base of cellular complications in diabetes mellitus. Parts of the figure were drawn using Servier Medical Art (https://smart.servier.com/, accessed on 14 December 2021).

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  Figure 3. The body pool of AGEs. Hyperglycemia, inflammation, and chronic kidney disease are major contributors to the body’s pool of AGEs. Furthermore, dietary sources of AGEs and tobacco add to the AGE pool, while detoxification systems include kidney function and the role played by soluble AGERs and DDOST that neutralize deleterious AGER signaling, along with enzyme systems, including the glyoxalase system, aldose reductase, and the lesser-known amadoriases.

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  Figure 4. Major influences of glycation on lipid metabolism and reverse cholesterol transport that favor atherogenesis. Alterations in lipid and lipoprotein metabolism induced by early and advanced glycation favor atherogenesis. In blood circulation, the lipolysis of chylomicrons and VLDLs by the lipoprotein lipase (LPL) is damaged by glycation, inducing plasma triglycerides elevation. The activity of CETP is also stimulated between glycated lipoproteins enabling more cholesterol to be transferred from HDLs to atherogenic lipoproteins and reducing HDL cholesterol. Glycated LDLs are taken up by macrophage scavenger receptors and by the advanced glycosylation end product-specific receptor (AGER). Advanced glycated albumin (AGE-albumin) induces, via AGERs, oxidative stress by enhancing the activity of NADPH oxidase 4 and mitochondrial systems and inflammation. Together, oxidative stress and inflammation lead to ER stress that triggers proteasomal and lysosomal degradation of the ABCA-1 compromising the cholesterol efflux to apo A-I and the generation of HDLs. The activity of (LCAT) is impaired by HDL glycation reducing the lipoprotein maturation. The accumulation of cholesterol and toxic…