Department of Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
Division of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
Heart Vessels. 2021 Dec;36(12):1923-1932. doi: 10.1007/s00380-021-01898-9. Epub 2021 Jul 26.
Oxidative stress, an inducer of apoptosis, plays a critical role in ischemia/reperfusion injury and atherosclerosis. We previously identified an apoptosis-inducing ligand, the post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A), 'oxidative stress-responsive apoptosis-inducing protein' (ORAIP). In this study, we investigated the role of ORAIP in patients with heterozygous familial hypercholesterolemia (HeFH), a leading cause of premature cardiovascular disease. We analyzed plasma ORAIP and oxidized low-density lipoprotein (oxLDL) levels in 60 patients with HeFH (60% male, 57.0 ± 13.6 years of age) and 20 patients with LDL-C hypercholesterolemia (DL, 85% male, 64.1 ± 13.3 years of age). The coronary artery atherosclerosis from the patients with HeFH who had a coronary artery bypass graft was investigated by double immunostaining. The plasma ORAIP levels in the patients with HeFH were significantly elevated compared to those in the patients with DL (73.5 ± 46.0 vs. 48.3 ± 21.4 ng/mL, p = 0.0277). The plasma oxLDL levels in HeFH patients were also elevated (156.8 ± 65.2 vs. 123.7 ± 46.6 mg/dL, p = 0.0461) compared to those in DL patients and correlated with maxLDL-C levels (R = 0.4454, p = 0.00648). Double-immunostaining of ORAIP and oxLDL in the coronary artery from patients with HeFH who had a coronary artery bypass graft showed that ORAIP and oxLDL were colocalized with apoptotic vascular smooth muscle cells in the atherosclerotic plaque. ORAIP plays a role in the development of oxidative stress-induced atherosclerosis and may be an important therapeutic target for plaque rupture in patients with HeFH.
氧化应激是细胞凋亡的诱导因素，在缺血/再灌注损伤和动脉粥样硬化中起着关键作用。我们之前鉴定了一种凋亡诱导配体，即翻译起始因子 5A（eIF5A）的翻译后修饰分泌形式，即“氧化应激反应性凋亡诱导蛋白”（ORAIP）。在这项研究中，我们研究了 ORAIP 在杂合家族性高胆固醇血症（HeFH）患者中的作用，HeFH 是导致早发性心血管疾病的主要原因。我们分析了 60 名 HeFH 患者（60%为男性，57.0±13.6 岁）和 20 名 LDL-C 高胆固醇血症（DL，85%为男性，64.1±13.3 岁）患者的血浆 ORAIP 和氧化型低密度脂蛋白（oxLDL）水平。通过双重免疫染色研究了 HeFH 患者的冠状动脉粥样硬化。与 DL 患者相比，HeFH 患者的血浆 ORAIP 水平显着升高（73.5±46.0 vs. 48.3±21.4 ng/mL，p=0.0277）。HeFH 患者的血浆 oxLDL 水平也升高（156.8±65.2 vs. 123.7±46.6 mg/dL，p=0.0461），与 maxLDL-C 水平相关（R=0.4454，p=0.00648）。对 HeFH 患者行冠状动脉旁路移植术的冠状动脉进行 ORAIP 和 oxLDL 的双重免疫染色显示，ORAIP 和 oxLDL 与动脉粥样硬化斑块中的凋亡血管平滑肌细胞共定位。ORAIP 在氧化应激诱导的动脉粥样硬化的发展中起作用，可能是 HeFH 患者斑块破裂的重要治疗靶点。
