Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors

Abstract

Reactive carbonyl compounds (RCCs) formed during lipid peroxidation and sugar glycoxidation, namely Advanced lipid peroxidation end products (ALEs) and Advanced Glycation end products (AGEs), accumulate with ageing and oxidative stress-related diseases, such as atherosclerosis, diabetes or neurodegenerative diseases. RCCs induce the 'carbonyl stress' characterized by the formation of adducts and cross-links on proteins, which progressively leads to impaired protein function and damages in all tissues, and pathological consequences including cell dysfunction, inflammatory response and apoptosis. The prevention of carbonyl stress involves the use of free radical scavengers and antioxidants that prevent the generation of lipid peroxidation products, but are inefficient on pre-formed RCCs. Conversely, carbonyl scavengers prevent carbonyl stress by inhibiting the formation of protein cross-links. While a large variety of AGE inhibitors has been developed, only few carbonyl scavengers have been tested on ALE-mediated effects. This review summarizes the signalling properties of ALEs and ALE-precursors, their role in the pathogenesis of oxidative stress-associated diseases, and the different agents efficient in neutralizing ALEs effects in vitro and in vivo. The generation of drugs sharing both antioxidant and carbonyl scavenger properties represents a new therapeutic challenge in the treatment of carbonyl stress-associated diseases.

Figure 1

Chemical formulae of some aldehydic compounds derived from lipid peroxidation, including saturated aldehydes, unsaturated aldehydes, 4-hydroxy-2-alkenals and dicarbonyls. These reactive carbonyl compounds are also advanced lipid peroxidation end product precursors.

Figure 2

Schematic steps of lipid peroxidation leading to the formation of secondary products and ALEs (Uchida, 2000; Aldini et al., 2006; Shibamoto, 2006). RCCs are able to react with proteins and other biological molecules, thereby forming ALEs. Stable products (such as alkanes) do not react with proteins. ALEs, advanced lipid peroxidation end products; RCCs, reactive carbonyl compounds.

Figure 3

Metabolic pathways leading to the formation of methylglyoxal (MGO) and of MGO adducts (Ramasamy et al., 2006). In addition to lipid peroxidation and glycoxidation, MGO can be formed as a by-product of glucose, glycerolipids and amino acids.

Figure 4

Schematic reactions of 4-HNE with proteins leading to the formation of 4-HNE-protein adducts. (1) Schiff base formation on primary amine (for example, lysin) leading to more complex compounds, such as pyrrole-Lys adducts and fluorescent cross-links. (2) Michael addition of 4-HNE on amino groups (Lys and His) or thiols (Cys or GSH), followed by cyclization and hemi-acetal or hemi-thioacetal formation (Sayre et al., 1993; Uchida 2000; Carini et al., 2004). 4-HNE, 4-hydroxynonenal; Lys, lysine; His, histidine; Cys, cysteine; GSH, glutathione.

Figure 5

Modification of LDL and formation of foam cells. ROS induce the oxidation of PUFA in LDLs. Lipid peroxidation leads to the formation of aldehydic compounds such as 4-HNE and MDA. These RCCs are able to react with lysin residues of apoB leading to modified apoB. The affinity of modified LDL for the apoB/E receptor decreases when apoB modification increases. Modified oxidized LDL are deviated towards the scavenger receptor pathway of macrophages, which are loaded with cholesterol esters and are transformed into foam cells, the signature of the initial step of atherosclerosis (Brown and Goldstein, 1983; Steinberg et al., 1989, 1997; Esterbauer et al., 1990, 1991). LDL, low-density lipoprotein, ROS, reactive oxygen species; PUFAs, polyunsaturated fatty acids; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde; RCCs, reactive carbonyl compounds.