Department of Integrated Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Mol Med. 2013 Jul 24;19(1):195-202. doi: 10.2119/molmed.2013.00037.
Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease.
促红细胞生成素（EPO）最初因其在造血中的关键作用而被确定为一种 I 型细胞因子，现已被证明具有非造血、组织保护作用，包括抑制动脉粥样硬化。然而，EPO 的促血栓形成作用阻碍了其在非贫血患者中的潜在临床应用。在本研究中，我们通过体外使用人脐静脉内皮细胞（HUVEC）和人单核细胞 THP-1 细胞以及体内使用 Watanabe 遗传性高脂血症自发性心肌梗死（WHHLMI）兔，研究了源自 EPO 的非促红细胞生成、组织保护化合物螺旋 B 表面肽（HBSP）的抗动脉粥样硬化作用。在 HUVEC 中，HBSP 抑制了 C 反应蛋白（CRP）诱导的凋亡（≈70%），CRP 是动脉粥样硬化的直接介质。通过使用小干扰 RNA 方法，发现 Akt 是 HBSP 介导的预防细胞凋亡的关键分子。HBSP 还减弱了 CRP 诱导的 THP-1 细胞中肿瘤坏死因子（TNF）-α和基质金属蛋白酶-9 的产生。在 WHHLMI 兔中，HBSP 显著抑制了冠状动脉粥样硬化病变的进展，病变的平均横截面积狭窄率（HBSP 为 21.3 ± 2.2%，而对照肽为 38.0 ± 2.7%）和通过增加 Akt 的激活抑制冠状动脉内皮细胞凋亡。此外，HBSP 治疗动物的冠状动脉粥样硬化病变中 TNF-α表达、M1 巨噬细胞数量和 M1/M2 巨噬细胞比例明显降低。总之，这些数据表明，HBSP 通过激活 Akt 抑制内皮细胞凋亡来抑制冠状动脉粥样硬化，这与降低 TNF-α产生和改变冠状动脉粥样硬化病变中巨噬细胞极化有关。由于 HBSP 没有 EPO 的促血栓形成作用，因此我们的研究可能为防止冠状动脉疾病进展提供了一种新的治疗策略。
