TY - JOUR
T1 - Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Suppressing Inflammatory Responses (Abstract)
AU - Wang, Luyao
AU - Zhang, Ning
AU - Liu, Jin
AU - Yang, Xin
AU - Yu, Yuanyuan
AU - Li, Dijie
AU - Jiang, Hewen
AU - Sun, Meiheng
AU - Li, Nanxi
AU - Ma, Daqing
AU - Huang, Yu
AU - Lu, Aiping
AU - Zhang, Baoting
AU - Zhang, Ge
N1 - This work was supported by the National Key R&D Program from the Ministry of Science and Technology of China (Project No. 2018YFA0800800), Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. 12102120, Project No. 12114416, Project No. 12103519, Project No. 12136616, Project No. 14103420, Project No. 14103121, and Project No. 14109721), Theme-based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. T12-201/20-R).
PY - 2023/5
Y1 - 2023/5
N2 - Background: Clinically, humanized anti-sclerostin antibody imposed cardiovascular events. Sclerostin demonstrated to protect cardiovascular system by inhibiting inflammatory responses, atherosclerosis and AA in SOSTki.ApoE-/- mice. The central residues of sclerostin form three loops. Sclerostin antibody targeted loop2 and loop3. In our published work, blockade of sclerostin antibody-sclerostin loop2 interaction attenuated antibody-induced aggravation of inflammatory responses, atherosclerosis and AA in ApoE-/- mice, whereas the cardiovascular protective effect of sclerostin was independent of loop3.Objective: To investigate how sclerostin participates in protecting cardiovascular system.Methods and Results: Our GWAS analysis of SOST variants in U.K.-Biobank indicated the association between sclerostin loop2-specific mutations and cardiovascular abnormalities. In sc-RNA-Seq, the proportion of aortic anti-inflammatory macrophage cluster was dramatically elevated in ApoE-/- mice after sclerostin knock-in (SOSTki.ApoE-/-), with Lrp8 (encoding ApoER2) being among the top-5 genes upregulated. Absence of ApoER2 was reported to lead to vascular inflammation and atherosclerosis. The inhibitory effects of sclerostin on macrophagic inflammatory responses in vitro, including inhibition of inflammatory cytokines and chemokines expression and promotion of macrophage conversion into anti-inflammatory phenotype, were dramatically attenuated upon ApoER2 silencing. In pull-down and SPR assays, sclerostin loop2 bound to ApoER2. After identification of their interaction residues, Lrp8-K749A mutation and ApoER2-XY peptide tool were designed to genetically and pharmacologically block sclerostin loop2-ApoER2 interaction. It was found that blockade of sclerostin loop2-ApoER2 interaction attenuated the suppressive effects of sclerostin on inflammatory responses in macrophages in vitro.Conclusion: Sclerostin loop2-ApoER2 interaction was required by sclerostin for suppressing inflammatory responses in macrophages.
AB - Background: Clinically, humanized anti-sclerostin antibody imposed cardiovascular events. Sclerostin demonstrated to protect cardiovascular system by inhibiting inflammatory responses, atherosclerosis and AA in SOSTki.ApoE-/- mice. The central residues of sclerostin form three loops. Sclerostin antibody targeted loop2 and loop3. In our published work, blockade of sclerostin antibody-sclerostin loop2 interaction attenuated antibody-induced aggravation of inflammatory responses, atherosclerosis and AA in ApoE-/- mice, whereas the cardiovascular protective effect of sclerostin was independent of loop3.Objective: To investigate how sclerostin participates in protecting cardiovascular system.Methods and Results: Our GWAS analysis of SOST variants in U.K.-Biobank indicated the association between sclerostin loop2-specific mutations and cardiovascular abnormalities. In sc-RNA-Seq, the proportion of aortic anti-inflammatory macrophage cluster was dramatically elevated in ApoE-/- mice after sclerostin knock-in (SOSTki.ApoE-/-), with Lrp8 (encoding ApoER2) being among the top-5 genes upregulated. Absence of ApoER2 was reported to lead to vascular inflammation and atherosclerosis. The inhibitory effects of sclerostin on macrophagic inflammatory responses in vitro, including inhibition of inflammatory cytokines and chemokines expression and promotion of macrophage conversion into anti-inflammatory phenotype, were dramatically attenuated upon ApoER2 silencing. In pull-down and SPR assays, sclerostin loop2 bound to ApoER2. After identification of their interaction residues, Lrp8-K749A mutation and ApoER2-XY peptide tool were designed to genetically and pharmacologically block sclerostin loop2-ApoER2 interaction. It was found that blockade of sclerostin loop2-ApoER2 interaction attenuated the suppressive effects of sclerostin on inflammatory responses in macrophages in vitro.Conclusion: Sclerostin loop2-ApoER2 interaction was required by sclerostin for suppressing inflammatory responses in macrophages.
KW - Sclerostin loop2
KW - ApoER2
KW - Cardiovascular protective effect
KW - Macrophage
KW - Inflammatory response
U2 - 10.1016/j.metabol.2023.155427
DO - 10.1016/j.metabol.2023.155427
M3 - Conference article
SN - 0026-0495
VL - 142
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
IS - Supplement
M1 - 155427
T2 - 20th Annual World Congress on Insulin Resistance Diabetes & Cardiovascular Disease, WCIRDC 2022
Y2 - 1 December 2022 through 3 December 2022
ER -
