Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, 2200, Denmark.
Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, 8010, Austria.
Redox Biol. 2023 Aug;64:102794. doi: 10.1016/j.redox.2023.102794. Epub 2023 Jun 27.
Continued oxidant production during chronic inflammation generates host tissue damage, with this being associated with pathologies including atherosclerosis. Atherosclerotic plaques contain modified proteins that may contribute to disease development, including plaque rupture, the major cause of heart attacks and strokes. Versican, a large extracellular matrix (ECM) chondroitin-sulfate proteoglycan, accumulates during atherogenesis, where it interacts with other ECM proteins, receptors and hyaluronan, and promotes inflammation. As activated leukocytes produce oxidants including peroxynitrite/peroxynitrous acid (ONOO/ONOOH) at sites of inflammation, we hypothesized that versican is an oxidant target, with this resulting in structural and functional changes that may exacerbate plaque development. The recombinant human V3 isoform of versican becomes aggregated on exposure to ONOO/ONOOH. Both reagent ONOO/ONOOH and SIN-1 (a thermal source of ONOO/ONOOH) modified Tyr, Trp and Met residues. ONOO/ONOOH mainly favors nitration of Tyr, whereas SIN-1 mostly induced hydroxylation of Tyr, and oxidation of Trp and Met. Peptide mass mapping indicated 26 sites with modifications (15 Tyr, 5 Trp, 6 Met), with the extent of modification quantified at 16. Multiple modifications, including the most extensively nitrated residue (Tyr), are within the hyaluronan-binding region, and associated with decreased hyaluronan binding. ONOO/ONOOH modification also resulted in decreased cell adhesion and increased proliferation of human coronary artery smooth muscle cells. Evidence is also presented for colocalization of versican and 3-nitrotyrosine epitopes in advanced (type II-III) human atherosclerotic plaques. In conclusion, versican is readily modified by ONOO/ONOOH, resulting in chemical and structural modifications that affect protein function, including hyaluronan binding and cell interactions.
在慢性炎症期间持续产生的氧化剂会导致宿主组织损伤，这与包括动脉粥样硬化在内的多种病理学有关。动脉粥样硬化斑块中含有可能导致疾病发展的修饰蛋白，包括斑块破裂，这是心脏病发作和中风的主要原因。神经角质蛋白聚糖（versican）是一种大型细胞外基质（ECM）硫酸软骨素蛋白聚糖，在动脉粥样硬化形成过程中会积累，与其他 ECM 蛋白、受体和透明质酸相互作用，并促进炎症反应。由于激活的白细胞会在炎症部位产生氧化剂，包括过氧亚硝酸盐/过氧亚硝酸（ONOO/ONOOH），我们假设 versican 是氧化剂的靶标，这会导致结构和功能发生变化，从而可能加剧斑块的发展。在暴露于 ONOO/ONOOH 时，重组人 V3 异构体的 versican 会聚集。ONOO/ONOOH 和 SIN-1（ONOO/ONOOH 的热来源）都修饰了 Tyr、Trp 和 Met 残基。ONOO/ONOOH 主要有利于 Tyr 的硝化，而 SIN-1 主要诱导 Tyr 的羟化以及 Trp 和 Met 的氧化。肽质量图谱显示有 26 个修饰位点（15 个 Tyr、5 个 Trp、6 个 Met），并定量了 16 个修饰程度。多个修饰部位（包括硝化程度最高的残基 Tyr）位于透明质酸结合区域内，并与透明质酸结合能力下降有关。ONOO/ONOOH 的修饰还导致人冠状动脉平滑肌细胞的黏附减少和增殖增加。还提供了证据表明，在晚期（II-III 型）人类动脉粥样硬化斑块中，versican 与 3-硝基酪氨酸表位发生共定位。总之，versican 很容易被 ONOO/ONOOH 修饰，导致化学和结构修饰，从而影响蛋白质功能，包括透明质酸结合和细胞相互作用。
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