Ning Da-Sheng, Ma Jian, Peng Yue-Ming, Li Yan, Chen Ya-Ting, Li Shang-Xuan, Liu Zui, Li Yu-Quan, Zhang Yi-Xin, Jian Yu-Peng, Ou Zhi-Jun, Ou Jing-Song
Division of Cardiac Surgery, Heart Center, The First Affiliated Hospital, Sun Yat-sen University, PR China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China; NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, PR China; Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, PR China.
Division of Hypertension and Vascular Diseases, Heart Center, The First Affiliated Hospital, Sun Yat-sen University, PR China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China; NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, PR China; Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, PR China.
Atherosclerosis. 2021 Jul;328:83-91. doi: 10.1016/j.atherosclerosis.2021.05.019. Epub 2021 May 31.
The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet.
Low-density lipoprotein (LDL) receptor null (LDLr) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured.
Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL.
Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.
载脂蛋白A-I模拟肽D-4F在其抗动脉粥样硬化作用中，通过尚未完全阐明的机制改善血管舒张功能。
给低密度脂蛋白（LDL）受体缺失（LDLr）小鼠喂食含或不含D-4F的西方饮食。然后我们测量了动脉粥样硬化病变形成、内皮型一氧化氮合酶（eNOS）磷酸化及其与热休克蛋白90（HSP90）的关联、一氧化氮（NO）和超氧阴离子（O）的产生，以及主动脉中四氢生物蝶呤（BH4）和GTP环水解酶1（GCH-1）的浓度。用人脐静脉内皮细胞（HUVECs）和主动脉分别用含或不含D-4F的氧化LDL（oxLDL）处理；随后，测量BH4和GCH-1浓度、NO和O的产生、eNOS与HSP90的关联以及内皮依赖性血管舒张功能。
出乎意料的是，在动脉粥样硬化中，eNOS磷酸化、eNOS-HSP90关联和O的产生增加，而BH4和GCH-1浓度以及NO产生减少。D-4F显著抑制动脉粥样硬化、eNOS磷酸化、eNOS-HSP90关联和O的生成，但增加NO产生以及BH4和GCH-1浓度。oxLDL降低NO产生以及BH4和GCH-1浓度，但增强O的生成和eNOS与HSP90的关联，并损害内皮依赖性血管舒张功能。D-4F抑制oxLDL的总体作用。
高胆固醇血症通过降低GCH-1浓度增强非偶联eNOS活性，从而降低BH4水平。D-4F通过增加GCH-1表达来提高BH4水平，并降低eNOS磷酸化和eNOS-HSP90关联，从而降低非偶联eNOS活性。我们的研究结果阐明了高胆固醇血症诱导动脉粥样硬化以及D-4F抑制该过程的新机制，提供了一种潜在的治疗方法。
