REVIEW Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents Giancarlo Aldini, Marica Orioli and Marina Carini Department of Pharmaceutical Sciences ‘‘Pietro Pratesi,’’ Universita ` degli Studi di Milano, Milan, Italy Received: March 16, 2011 Revised: May 12, 2011 Accepted: June 15, 2011 Acrolein (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. 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 demon- strating 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 modifica- tions. 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. Keywords: Acrolein / Aldehyde-sequestering agents / Neurodegenerative diseases / Protein adducts / Reactive carbonyl species 1 Introduction Protein modification by reactive carbonyl species (RCS), especially those generated by peroxidation of poly- unsaturated fatty acids (PUFAs), in the last few years has gained an even greater importance, in view of the emerging deleterious role of the RCS–protein adducts in the aetiology and/or progression of several human diseases, such as cardiovascular (atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (Alzheimer’s disease (AD), Parkinson’s disease [PD], and cerebral ische- mia). Although protein carbonylation and the chemistry of the reactions that give rise to carbonyl groups are quite well characterized [1], the overall biology of oxidative protein modifications remains complex and incompletely defined. Among the variety of RCS (three to nine carbons in length) generated by oxidative decomposition of PUFAs, the a,b-unsaturated aldehyde acrolein (ACR) is by far the strongest electrophile, showing the highest reactivity toward nucleophilic sites on proteins [2, 3]. Although lipid perox- idation generates far more 4-hydroxy-trans-2-nonenal (HNE) than ACR [4], it has been reported, based on the urinary daily excretion, that production of ACR metabolites in humans is 10 2 -fold greater than that of HNE metabolites [4]. Abbreviations: ACR, acrolein; AGE, advanced glycoxidation end product; ALE, advanced lipoxidation end product; apoA-1, apolipoprotein A-1; CAR, carnosine; FDP-Lys, N e -(3-formyl-3,4- dehydropiperidino)lysine; GSH, glutathione; GST, GSH-S-trans- ferase; HGF, human gingival fibroblast; HNE, 4-hydroxy-trans-2- nonenal; HY, hydralazine; MP-Lys, N e -(3-methylpyridinium) lysine; NAC, N-acetylcysteine; NO, nitric oxide; NQO1, NAD(P)H:- quinone oxidoreductase 1; PC-ACR, protein-conjugated acrolein; PD, Parkinson’s disease; RCS, reactive carbonyl species Correspondence: Professor Marina Carini, Department of Phar- maceutical Sciences ‘‘Pietro Pratesi,’’ Universita ` degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy E-mail: marina.carini@unimi.it Fax: 139-250319359 & 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com Mol. Nutr. Food Res. 2011, 55, 1301–1319 1301 DOI 10.1002/mnfr.201100182