Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway.
Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway.
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抗 ATR001 单克隆抗体通过 β-arrestin2 途径改善动脉粥样硬化。
DOI：
10.1016/j.bbrc.2021.01.054
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Chen Xiao
中科院分区：
文献类型：
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作者：
Wang Yingxuan;Fan Zhiran;Xu Chanjuan;Yan Xiaole;Zhou Yanzhao;Qiu Zhihua;Yuan Qingchen;Zheng Jiayu;Liao Yuhua;Chen Xiao
我们之前的研究开发了ATRQβ-001疫苗，该疫苗靶向血管紧张素Ⅱ（AngⅡ）受体1型（AT1R）肽atr01。ATRQβ-001疫苗能诱导抗atr01单克隆抗体（McAb-ATR）的产生，在不反馈激活肾素血管紧张素系统（RAS）的情况下抑制动脉粥样硬化。本研究旨在探讨McAb-ATR在改善动脉粥样硬化中的作用机制。方法构建sat1r - ko HEK293T细胞株，鉴定McAb-ATR特异性和atrq - β-001疫苗的关键位点。采用β -arrestin1敲除（Arrb1−/−）小鼠、β -arrestin2敲除（Arrb2−/−）小鼠和低密度脂蛋白受体敲除（LDLr−/−）小鼠检测mabb - atr影响的潜在信号通路。我们还研究了McAb-ATR在β -阻滞蛋白和G蛋白（Gqor Gi2/i3）信号转导事件中的作用。结果smcab - atr可特异性结合AT1R第二细胞外环（ECL2）的phe182 - his183 - tyr184位点。在移植arrb2 - / -小鼠骨髓（BM）和arrb2 - / -小鼠骨髓源性巨噬细胞（bmdm）的ldlr - / -小鼠中，mabb - atr的抗动脉粥样硬化作用消失。此外，mabb - atr抑制β -arrestin2依赖性细胞外信号调节的激酶1/2 （ERK1/2）磷酸化，并促进β -arrestin2介导的核因子κB p65 （NFκB p65）失活。与传统的AT1R阻滞剂（arb）相比，McAb-ATR不抑制AngⅡ诱导的异三聚体G蛋白（Gqor Gi2/i3）的解偶联和gq依赖性的细胞内Ca2+释放，也不引起RAS反馈激活。结论McAb-ATR通过调节β -arrestin2，在不影响Gqor Gi2/i3通路的情况下改善动脉粥样硬化。由于AT1R的高选择性和与β -arrestin2的偏倚相互作用，McAb-ATR可以作为治疗动脉粥样硬化的新策略。
BackgroundOur previous study developed ATRQβ-001 vaccine, which targets peptide ATR001 from angiotensin Ⅱ (Ang Ⅱ) receptor type 1 (AT1R). The ATRQβ-001 vaccine could induce the production of anti-ATR001 monoclonal antibody (McAb-ATR) and inhibit atherosclerosis without feedback activation of the renin-angiotensin system (RAS). This study aims at investigating the underexploited mechanisms of McAb-ATR in ameliorating atherosclerosis.MethodsAT1R–KO HEK293T cell lines were constructed to identify the specificity of McAb-ATR and key sites of ATRQβ-001 vaccine. Beta-arrestin1 knock-out (Arrb1−/−) mice, Beta-arrestin2 knock-out (Arrb2−/−) mice, and low-density lipoprotein receptor knock-out (LDLr−/−) mice were used to detect potential signaling pathways affected by McAb-ATR. The role of McAb-ATR in beta-arrestin and G proteins (Gqor Gi2/i3) signal transduction events was also investigated.ResultsMcAb-ATR could specifically bind to the Phe182-His183-Tyr184site of AT1R second extracellular loop (ECL2). The anti-atherosclerotic effect of McAb-ATR disappeared inLDLr−/−mice transplanted withArrb2−/−mouse bone marrow (BM) and BM-derived macrophages (BMDMs) fromArrb2−/−mice. Furthermore, McAb-ATR inhibited beta-arrestin2-dependent extracellular signal regulated kinase1/2 (ERK1/2) phosphorylation, and promoted beta-arrestin2-mediated nuclear factor kappa B p65 (NFκB p65) inactivity. Compared with conventional AT1R blockers (ARBs), McAb-ATR did not inhibit Ang Ⅱ-induced uncoupling of heterotrimeric G proteins (Gqor Gi2/i3) and Gq-dependent intracellular Ca2+release, nor cause RAS feedback activation.ConclusionsThrough regulating beta-arrestin2, McAb-ATR ameliorates atherosclerosis without affecting Gqor Gi2/i3pathways. Due to high selectivity for AT1R and biased interaction with beta-arrestin2, McAb-ATR could serve as a novel strategy for treating atherosclerosis.
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1 型血管紧张素受体疫苗可预防链脲佐菌素诱发的糖尿病肾病
DOI：
10.1007/s00109-015-1343-6
发表时间：
2016-02
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
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作者：
Ding D;Du Y;Qiu Z;Yan S;Chen F;Wang M;Yang S;Zhou Y;Hu X;Deng Y;Wang S;Wang L;Zhang H;Wu H;Yu X;Zhou Z;Liao Y;Chen X
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Chen X
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20.1
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Randolph GJ
DOI：
10.1073/pnas.0402851101
发表时间：
2004-06
影响因子：
11.1
作者：
D. Witherow;T. Garrison;W. Miller;R. Lefkowitz
通讯作者：
D. Witherow;T. Garrison;W. Miller;R. Lefkowitz
影响因子：
24
作者：
Savarese, Gianluigi;Costanzo, Pierluigi;Perrone-Filardi, Pasquale
通讯作者：
Perrone-Filardi, Pasquale
影响因子：
7.7
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