Division of Nephrology, University of Michigan, Ann Arbor, MI 48105, USA.
Ann Rheum Dis. 2013 Oct;72(10):1725-31. doi: 10.1136/annrheumdis-2012-202033. Epub 2013 Jan 12.
Phagocyte-derived myeloperoxidase (MPO) and pro-inflammatory high density lipoprotein (HDL) associate with rheumatoid arthritis (RA), but the link between MPO and HDL has not been systematically examined. In this study, we investigated whether MPO can oxidise HDL and determined MPO-specific oxidative signature by apoA-1 by peptide mapping in RA subjects with and without known cardiovascular disease (CVD).
Two MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were quantified by tandem mass spectrometry (MS/MS) in in vitro model system studies and in plasma and HDL derived from healthy controls and RA subjects. MPO levels and cholesterol efflux were determined. Site-specific nitration and chlorination of apoA-1 peptides were quantified by MS/MS.
RA subjects demonstrated higher levels of MPO, MPO-oxidised HDL and diminished cholesterol efflux. There was marked increase in MPO-specific 3-chlorotyrosine and 3-nitrotyrosine content in HDL in RA subjects consistent with specific targeting of HDL, with increased nitration in RA subjects with CVD. Cholesterol efflux capacity was diminished in RA subjects and correlated inversely with HDL 3-chlorotyrosine suggesting a mechanistic role for MPO. Nitrated HDL was elevated in RACVD subjects compared with RA subjects without CVD. Oxidative peptide mapping revealed site-specific unique oxidation signatures on apoA-1 for RA subjects with and without CVD.
We report an increase in MPO-mediated HDL oxidation that is regiospecific in RA and accentuated in those with CVD. Decreased cholesterol efflux capacity due to MPO-mediated chlorination is a potential mechanism for atherosclerosis in RA and raises the possibility that oxidant resistant forms of HDL may attenuate this increased risk.
吞噬细胞来源的髓过氧化物酶（MPO）和促炎型高密度脂蛋白（HDL）与类风湿关节炎（RA）相关，但 MPO 与 HDL 之间的联系尚未得到系统研究。在这项研究中，我们调查了 MPO 是否可以氧化 HDL，并通过 RA 患者和无已知心血管疾病（CVD）患者的载脂蛋白 A-1 肽图分析确定 MPO 特异性氧化特征。
通过串联质谱（MS/MS）在体外模型系统研究和来自健康对照者和 RA 患者的血浆和 HDL 中定量检测两种 MPO 氧化产物 3-氯酪氨酸和 3-硝基酪氨酸。测定 MPO 水平和胆固醇外排。通过 MS/MS 定量测定载脂蛋白 A-1 肽的特异性硝化和氯化。
RA 患者表现出更高的 MPO、MPO 氧化的 HDL 和胆固醇外排减少。RA 患者的 HDL 中 MPO 特异性 3-氯酪氨酸和 3-硝基酪氨酸含量明显增加，表明 HDL 有明确的靶向作用，CVD 患者的硝化作用增加。RA 患者的胆固醇外排能力下降，与 HDL 3-氯酪氨酸呈负相关，提示 MPO 具有机制作用。与无 CVD 的 RA 患者相比，RA-CVD 患者的硝化 HDL 升高。氧化肽图显示 RA 患者和 CVD 患者载脂蛋白 A-1 上存在特定的、独特的氧化特征。
我们报告了 MPO 介导的 HDL 氧化增加，在 RA 中具有区域特异性，在 CVD 患者中更为明显。由于 MPO 介导的氯化导致胆固醇外排能力下降，可能是 RA 中动脉粥样硬化的潜在机制，并提示抗氧化剂抵抗型 HDL 可能减轻这种增加的风险。
