Xu Gang, Watanabe Takuya, Iso Yoshitaka, Koba Shinji, Sakai Tetsuo, Nagashima Masaharu, Arita Shigeko, Hongo Shigeki, Ota Hidekazu, Kobayashi Youichi, Miyazaki Akira, Hirano Tsutomu
Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
Circ Res. 2009 Aug 28;105(5):500-10. doi: 10.1161/CIRCRESAHA.109.193870. Epub 2009 Jul 30.
Human heregulins, neuregulin-1 type I polypeptides that activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, are expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester accumulation, is modulated by scavenger receptor class A (SR-A), acyl-coenzyme A:cholesterol acyltransferase (ACAT)1, and ATP-binding cassette transporter (ABC)A1.
The present study clarified the roles of heregulins in macrophage foam cell formation and atherosclerosis.
Plasma heregulin-beta(1) levels were significantly decreased in 31 patients with acute coronary syndrome and 33 patients with effort angina pectoris compared with 34 patients with mild hypertension and 40 healthy volunteers (1.3+/-0.3, 2.0+/-0.4 versus 7.6+/-1.4, 8.2+/-1.2 ng/mL; P<0.01). Among all patients with acute coronary syndrome and effort angina pectoris, plasma heregulin-beta(1) levels were further decreased in accordance with the severity of coronary artery lesions. Expression of heregulin-beta(1) was observed at trace levels in intracoronary atherothrombosis obtained by aspiration thrombectomy from acute coronary syndrome patients. Heregulin-beta(1), but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein-induced cholesterol ester accumulation in primary cultured human monocyte-derived macrophages by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta(1) significantly decreased endocytic uptake of [(125)I]acetylated low-density lipoprotein and ACAT activity, and increased cholesterol efflux to apolipoprotein (Apo)A-I from human macrophages. Chronic infusion of heregulin-beta(1) into ApoE(-/-) mice significantly suppressed the development of atherosclerotic lesions.
This study provided the first evidence that heregulin-beta(1) inhibits atherogenesis and suppresses macrophage foam cell formation via SR-A and ACAT1 downregulation and ABCA1 upregulation.
人神经调节蛋白，即激活神经胶质细胞、神经元及心肌细胞增殖、分化和存活的I型神经调节蛋白1多肽，在人类冠状动脉粥样硬化病变内的巨噬细胞泡沫细胞中表达。巨噬细胞泡沫细胞形成以胆固醇酯蓄积为特征，受A类清道夫受体（SR-A）、酰基辅酶A：胆固醇酰基转移酶（ACAT）1和ATP结合盒转运体（ABC）A1调控。
本研究阐明了神经调节蛋白在巨噬细胞泡沫细胞形成及动脉粥样硬化中的作用。
与34例轻度高血压患者和40名健康志愿者相比，31例急性冠状动脉综合征患者和33例劳力性心绞痛患者的血浆神经调节蛋白-β(1)水平显著降低（分别为1.3±0.3、2.0±0.4 ng/mL，而7.6±1.4、8.2±1.2 ng/mL；P<0.01）。在所有急性冠状动脉综合征和劳力性心绞痛患者中，血浆神经调节蛋白-β(1)水平随冠状动脉病变严重程度进一步降低。在通过急性冠状动脉综合征患者血栓抽吸术获得的冠状动脉内动脉粥样血栓形成中观察到神经调节蛋白-β(1)的微量表达。神经调节蛋白-β(1)而非神经调节蛋白-α，通过在mRNA和蛋白水平降低SR-A和ACAT1表达并增加ABCA1表达，显著减少原代培养的人单核细胞衍生巨噬细胞中乙酰化低密度脂蛋白诱导的胆固醇酯蓄积。神经调节蛋白-β(1)显著降低[(125)I]乙酰化低密度脂蛋白的内吞摄取及ACAT活性，并增加人巨噬细胞向载脂蛋白（Apo）A-I的胆固醇流出。向ApoE(-/-)小鼠长期输注神经调节蛋白-β(1)显著抑制动脉粥样硬化病变的发展。
本研究首次证明神经调节蛋白-β(1)通过下调SR-A和ACAT1及上调ABCA1抑制动脉粥样硬化形成并抑制巨噬细胞泡沫细胞形成。
