TY - JOUR
T1 - Angiotensin II modification by decomposition products of linoleic acid-derived lipid hydroperoxide
AU - Takahashi, Ryo
AU - Goto, Takaaki
AU - Oe, Tomoyuki
AU - Lee, Seon Hwa
N1 - Funding Information:
This work was supported in part by a Grant-in-aid for Challenging Exploratory Research (to T.O., 21659035 for 2009–2010) and Grants-in-aid for Scientific Research (C) (to S.H.L., 22590130 for 2010–2012; to T.G., 40344684 for 2012–2014) from the Japan Society for the Promotion of Science .
Publisher Copyright:
© 2015 Elsevier Ireland Ltd.
PY - 2015/7/2
Y1 - 2015/7/2
N2 - Abstract Polyunsaturated fatty acids are highly susceptible to oxidation induced by reactive oxygen species and enzymes, leading to the formation of lipid hydroperoxides. The linoleic acid (LA)-derived hydroperoxide, 13-hydroperoxyoctadecadienoic acid (HPODE) undergoes homolytic decomposition to reactive aldehydes, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal, trans-4,5-epoxy-2(E)-decenal (EDE), and 4-hydroperoxy-2(E)-nonenal (HPNE), which can covalently modify peptides and proteins. ONE and HNE have been shown to react with angiotensin (Ang) II (DRVYIHPF) and modify the N-terminus, Arg2, and His6. ONE-derived pyruvamide-Ang II (Ang P) alters the biological activities of Ang II considerably. The present study revealed that EDE and HPNE preferentially modified the N-terminus and His6 of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His6(EDE)]-Ang II, hydrated forms were detected as major products, suggesting considerable involvement of the vicinal dihydrodiol (formed by epoxide hydration) in EDE-derived protein modification in vivo. Substantial amounts of [N-(EDE - H2O)]-Ang II isomers were also formed and their synthetic pathway might involve the tautomerization of a carbinolamine intermediate, followed by intramolecular cyclization and dehydration. The main HPNE-derived products were [His6(HPNE)]-Ang II and [N-(HPNE - H2O)]-Ang II. However, ONE, HNE, and malondialdehyde-derived modifications were dominant, because HPNE is a precursor of these aldehydes. A mixture of 13-HPODE and [13C18]-13-HPODE (1:1) was then used to determine the major modifications derived from LA peroxidation. The characteristic doublet (1:1) observed in the mass spectrum and the mass difference of the [M + H]+ doublet aided the identification of Ang P (N-terminal α-ketoamide), [N-ONE]-Ang II (4-ketoamide), [Arg2(ONE - H2O)]-Ang II, [His6(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole), [His6(HPNE)]-Ang II, [N-(9,12-dioxo-10(E)-dodecenoic acid)]-Ang II, and [His6(9-hydroxy-12-oxo-10(E)-decenoic acid)]-Ang II as the predominant LA-derived modifications. These modifications could represent the majority of lipid-derived modifications to peptides and proteins in biological systems.
AB - Abstract Polyunsaturated fatty acids are highly susceptible to oxidation induced by reactive oxygen species and enzymes, leading to the formation of lipid hydroperoxides. The linoleic acid (LA)-derived hydroperoxide, 13-hydroperoxyoctadecadienoic acid (HPODE) undergoes homolytic decomposition to reactive aldehydes, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal, trans-4,5-epoxy-2(E)-decenal (EDE), and 4-hydroperoxy-2(E)-nonenal (HPNE), which can covalently modify peptides and proteins. ONE and HNE have been shown to react with angiotensin (Ang) II (DRVYIHPF) and modify the N-terminus, Arg2, and His6. ONE-derived pyruvamide-Ang II (Ang P) alters the biological activities of Ang II considerably. The present study revealed that EDE and HPNE preferentially modified the N-terminus and His6 of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His6(EDE)]-Ang II, hydrated forms were detected as major products, suggesting considerable involvement of the vicinal dihydrodiol (formed by epoxide hydration) in EDE-derived protein modification in vivo. Substantial amounts of [N-(EDE - H2O)]-Ang II isomers were also formed and their synthetic pathway might involve the tautomerization of a carbinolamine intermediate, followed by intramolecular cyclization and dehydration. The main HPNE-derived products were [His6(HPNE)]-Ang II and [N-(HPNE - H2O)]-Ang II. However, ONE, HNE, and malondialdehyde-derived modifications were dominant, because HPNE is a precursor of these aldehydes. A mixture of 13-HPODE and [13C18]-13-HPODE (1:1) was then used to determine the major modifications derived from LA peroxidation. The characteristic doublet (1:1) observed in the mass spectrum and the mass difference of the [M + H]+ doublet aided the identification of Ang P (N-terminal α-ketoamide), [N-ONE]-Ang II (4-ketoamide), [Arg2(ONE - H2O)]-Ang II, [His6(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole), [His6(HPNE)]-Ang II, [N-(9,12-dioxo-10(E)-dodecenoic acid)]-Ang II, and [His6(9-hydroxy-12-oxo-10(E)-decenoic acid)]-Ang II as the predominant LA-derived modifications. These modifications could represent the majority of lipid-derived modifications to peptides and proteins in biological systems.
KW - Angiotensin II
KW - Linoleic acid hydroperoxide
KW - Lipid peroxidation
KW - Mass spectrometry
KW - Peptide modification
KW - Reactive aldehydes
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U2 - 10.1016/j.cbi.2015.06.029
DO - 10.1016/j.cbi.2015.06.029
M3 - Article
C2 - 26111765
AN - SCOPUS:84933516123
VL - 239
SP - 87
EP - 99
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
SN - 0009-2797
M1 - 7404
ER -