Da-Sheng Ning1, Jian Ma1, Yue-Ming Peng1, Yan Li1, Ya-Ting Chen1, Shang-Xuan Li1, Zui Liu1, Yu-Quan Li1, Yi-Xin Zhang2, Yu-Peng Jian1, Zhi-Jun Ou2, Jing-Song Ou3. 1. 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. 2. 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. 3. 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; Guangdong Provincial Key Laboratory of Brain Function and Disease,Guangzhou, 510080, PR China. Electronic address: oujs@mail.sysu.edu.cn.
Abstract
BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: 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 (O2•-) 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 O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- 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 O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: 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.
BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: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 (O2•-) 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 O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- 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 O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: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.
Authors: Hui Jiang; Yongwen Zhou; Seyed M Nabavi; Amirhossein Sahebkar; Peter J Little; Suowen Xu; Jianping Weng; Jianjun Ge Journal: Front Cardiovasc Med Date: 2022-06-01