Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; IM Sechenov First Moscow State Medical University, Moscow, Russia.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
Free Radic Biol Med. 2021 Jan;162:266-273. doi: 10.1016/j.freeradbiomed.2020.10.024. Epub 2020 Oct 21.
Lipid peroxidation results in generation of a variety of lipid hydroperoxides and other highly reactive species that covalently modify proteins, nucleic acids, and other lipids, thus resulting in lipotoxicity. Although biological relevance of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) is well studied, the existing data on the role of isolevuglandins (isoLGs) in pathology are insufficient. Therefore, the objective of the present study was to review the existing data on biological effects of isoLG and isoLG adducts and their role in multiple diseases. Sixty four highly reactive levuglandin-like γ-ketoaldehyde (γ-KA, or isoketals, IsoK, or isolevuglandins, IsoLG) regio- and stereo-isomers are formed as products of arachidonic acid oxidation. IsoLGs react covalently with lysyl residues of proteins to form a stable adduct and intramolecular aminal, bispyrrole, and trispyrrole cross-links. Phosphatidylethanolamine was also shown to be the target for isoLG binding as compared to proteins and DNA. Free IsoLGs are not detectable in vivo, although isolevuglandin adduction to amino acid residues of particular proteins may be evaluated with liquid chromatography-tandem mass spectrometry. Adducts formed were shown to play a significant role in the development and maintenance of oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and inflammation. These, and more specific molecular pathways, link isoLG and isoLG-adduct formation to develop a variety of pathologies, including cardiovascular diseases (atherosclerosis, hypertension, heart failure), obesity and diabetes, cancer, neurodegeneration, eye diseases (retinal degeneration and glaucoma), as well as ageing. Hypothetically, isoLGs and isoLG adduct formation may be considered as the potential target for treatment of oxidative stress-related diseases.
脂质过氧化会导致各种脂质氢过氧化物和其他高反应性物质的产生，这些物质会使蛋白质、核酸和其他脂质发生共价修饰，从而导致脂毒性。虽然 4-羟基壬烯醛（4-HNE）和丙二醛（MDA）的生物学相关性得到了很好的研究，但关于异勒维因（isoLG）在病理学中的作用的现有数据还不够充分。因此，本研究的目的是综述 isoLG 和 isoLG 加合物的生物学效应及其在多种疾病中的作用的现有数据。64 种高度反应性的莱格朗德酮样γ-酮醛（γ-KA，或异酮，IsoK，或异勒维因，IsoLG）区域和立体异构体是作为花生四烯酸氧化的产物形成的。IsoLG 与赖氨酸残基共价反应，形成稳定的加合物和分子内亚胺、双吡咯和三吡咯交联。与蛋白质和 DNA 相比，还表明磷脂乙醇胺是 IsoLG 结合的靶标。虽然可以用液相色谱-串联质谱法评估特定蛋白质的氨基酸残基上的异勒维因加合物，但在体内无法检测到游离 IsoLG。形成的加合物在氧化应激、内质网应激、线粒体功能障碍和炎症的发展和维持中发挥着重要作用。这些，以及更具体的分子途径，将 IsoLG 和 IsoLG 加合物的形成与多种病理学联系起来，包括心血管疾病（动脉粥样硬化、高血压、心力衰竭）、肥胖和糖尿病、癌症、神经退行性疾病、眼部疾病（视网膜变性和青光眼）以及衰老。从理论上讲，可以将 IsoLG 加合物的形成视为治疗与氧化应激相关疾病的潜在靶点。
