Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Abstract

Acrolein (ACR) is a toxic and highly reactive α,β-unsaturated aldehyde widely distributed in the environment as a common pollutant and generated endogenously mainly by lipoxidation reactions. Its biological effects are due to its ability to react with the nucleophilic sites of proteins, to form covalently modified biomolecules which are thought to be involved as pathogenic factors in the onset and progression of many pathological conditions such as cardiovascular and neurodegenerative diseases. Functional impairment of structural proteins and enzymes by covalent modification (crosslinking) and triggering of key cell signalling systems are now well-recognized signs of cell and tissue damage induced by reactive carbonyl species (RCS). In this review, we mainly focus on the in vitro and in vivo evidence demonstrating the ability of ACR to covalently modify protein structures, in order to gain a deeper insight into the dysregulation of cellular and metabolic pathways caused by such modifications. In addition, by considering RCS and RCS-modified proteins as drug targets, this survey will provide an overview on the newly developed molecules specifically tested for direct or indirect ACR scavenging, and the more significant studies performed in the last years attesting the efficacy of compounds already recognized as promising aldehyde-sequestering agents.

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

“…ACR is a toxic and highly reactive a,b-unsaturated aldehyde widely distributed in the environment as a common pollutant and generated endogenously mainly by lipoxidation reactions. The biological effects of ACR are due to its ability to react with the nucleophilic sites of proteins, to form covalently modified biomolecules, which are thought to be involved in the onset and progression of many pathological conditions, such as cardiovascular and neurodegenerative diseases [36].…”

Acrolein, an α,β-Unsaturated Carbonyl, Inhibits Both Growth and PSII Activity in the CyanobacteriumSynechocystissp. PCC 6803

“…7,10,11,18,48,49) For example, it reacts with Lys in human low-density lipoprotein, where acrolein-Lys adducts are formed. 11) Furthermore, the formation of acrolein-Cys adducts inactivates tyrosine phosphatase.…”

“…6,[12][13][14][15][16][17] The accumulation of acrolein modifies the amino residues in the proteins, stimulating carbonylation in human and rat cells. 18,19) , -Unsaturated carbonyls also accumulate in plant cells after exposure to high-temperature stress. [20][21][22] These are highly reactive in plant cells.…”

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

“…As strong electrophiles, these species deplete GSH and attack the proteome to form deleterious protein adducts (West and Marnett, 2006;Negre-Salvayre et al, 2008). Seeking to offset such damage, researchers have explored the use of nucleophilic drugs to scavenge "free" carbonyls within cells, attempting to attenuate macromolecular adduction and any accompanying toxicity (Aldini et al, 2007(Aldini et al, , 2011aBurcham, 2008). Agents that have attracted attention as "carbonyl scavengers" include the neuroprotectant evaradone (Aldini et al, 2010), the antidepressant phenelzine (Wood et al, 2006), the hypoglycemic metformin (Ruggiero-Lopez et al, 1999), the antimicrobial isoniazid (Galvani et al, 2008), the dipeptide carnosine (Aldini et al, 2011b), the vasodilator hydralazine , the antioxidant ascorbate (Kesinger et al, 2010), and various biogenic polyphenolic compounds (Zhu et al, 2009).…”