Abstract
Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process.The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity.
Highlights
In recent years, it has become evident that lipid peroxidation (LPO) products are involved in the intracellular signaling mechanisms that determine the cell’s final fate [1]
Because HSP60 is well known as a vehicle of the presentation of endogenous peptides to T cells [132] and as a target of autoimmune responses in atherosclerosis [133], we proposed that the modification of HSP60 with HNE may both contribute to the oxidative stress-driven inflammation of arterial intima and act as a switchover to immunity-driven chronic inflammation in atherosclerosis [131]
We focus here on the adducts of LPO products with DNA, it is worth mentioning that Toyoda et al, while investigating the role of HNE-modified proteins as a possible source of anti-DNA antibodies, detected antibodies against HNE-modified bovine serum albumin (BSA) in the sera of patients with systemic lupus erythematosus (SLE), Sjögren syndrome (SS), rheumatoid arthritis (RA), systemic sclerosis and idiopathic inflammatory miopathies, and HNE-specific epitopes in the epidermis and dermis of patients with SLE, pemphigus vulgaris and contact dermatitis [170]
Summary
HNE-dGuo: 1,N2-propano-2'-deoxyguanosine adduct of HNE 9(S)-HPODE: 9(S)-hydroperoxy-9,11-octadecadienoic acid 13(S)-HPODE: 13(S)-hydroperoxy-9,11-octadecadienoic acid MAP kinases: mitogen-activated protein kinases MCL1: induced myeloid leukemia cell differentiation protein Mcl-1 M1dA: N6-(3-oxoprenyl)-deoxyadenosine M1dC: N4-(3-oxoprenyl)-deoxycytidine M1dG: malondialdehyde-2'-deoxyguanosine, or pyrimido[1,2- ]purine-10(3H)-one-2'-deoxyribose -OH-PdG: -hydroxy-1,N2-propano-2'-deoxyguanosine -OH-PdG: -hydroxy-1,N2-propano-2'-deoxyguanosine ONE-dAde: 7-(2"-oxoheptyl)-1,N6-etheno-2'-deoxyadenosine ONE-dCyt: 7-(2"-oxoheptyl)-3,N4-etheno-2'-deoxycytidine ONE-dGuo: 7-(2"-oxoheptyl)-1,N2-etheno-2'-deoxyguanosine OPdG: N2-(3-oxoprop-1-enyl)-deoxyguanosine 8-oxo-dGuo: 8-oxo-hydroxy-7,8-dihydro-2'-deoxyguanosine PdG: N2-(3-oxopropyl)-deoxyguanosine PEITC: beta-phenylethyl isothiocyanate PPAR gamma: peroxisome proliferator-activated receptor gamma
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