title: Angiotensin II modification by decomposition products of linoleic acid-derived lipid hydroperoxide.
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, Arg(2), and His(6). 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 His(6) of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His(6)(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 [His(6)(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 [(13)C18]-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), [Arg(2)(ONE-H2O)]-Ang II, [His(6)(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole), [His(6)(HPNE)]-Ang II, [N-(9,12-dioxo-10(E)-dodecenoic acid)]-Ang II, and [His(6)(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.
authors.affiliation: Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Goto
authors.affiliation: Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan. Electronic address: t-oe@mail.pharm.tohoku.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oe
authors.affiliation: Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan. Electronic address: sh-lee@mail.pharm.tohoku.ac.jp.
authors.forename: Seon Hwa
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000804:Angiotensin II / Q000737:chemistry*; D001205:Ascorbic Acid / Q000737:chemistry; D001218:Aspartame / Q000737:chemistry; D002247:Carbon Isotopes / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D007536:Isomerism; D008041:Linoleic Acids / Q000737:chemistry*; D008054:Lipid Peroxides / Q000737:chemistry*; D008315:Malondialdehyde / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: C096140:4,5-epoxy-2-decenal; D000447:Aldehydes; D002247:Carbon Isotopes; D004852:Epoxy Compounds; D008041:Linoleic Acids; D008054:Lipid Peroxides; D000804:Angiotensin II; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C008285:linoleic acid hydroperoxide; D008315:Malondialdehyde; C547259:4-hydroperoxy-2-nonenal; D001205:Ascorbic Acid; D001218:Aspartame
keywords: Angiotensin II; Linoleic acid hydroperoxide; Lipid peroxidation; Mass spectrometry; Peptide modification; Reactive aldehydes