Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody-induced hypertension in the rabbit.
Novel retro-inverso peptide inhibitor reverses angiotensin receptor autoantibody-induced hypertension in the rabbit.
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DOI：
10.1161/hypertensionaha.114.05037
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Yu X
中科院分区：
文献类型：
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作者：
Li H;Kem DC;Zhang L;Huang B;Liles C;Benbrook A;Gali H;Veitla V;Scherlag BJ;Cunningham MW;Yu X
激活血管紧张素 II 1 型受体 (AT1R) 自身抗体与高血压有关。我们研究了免疫兔体内产生的 AT1R 抗体是否会激活 AT1R 并通过对脉管系统的直接收缩作用导致高血压；以及是否可以通过新型诱饵肽来阻断它们。使用含有 AT1R 表位 AFHYESQ（AT1R 激活自身抗体的受体结合表位）的多抗原肽来免疫 6 只兔子。在 AT1R 转染细胞中分析 AT1R 抗体活性，并使用分离的灌注大鼠提睾肌抗性小动脉测定其收缩效应。测试了逆反 D-氨基酸 (RID) 表位模拟肽的体外和体内 AT1R 抗体抑制作用。所有免疫动物均产生高 AT1R 抗体滴度并出现血压升高。免疫后未观察到测得的血液化学值发生变化。兔抗 AT1R 血清在转染细胞中诱导显着的 AT1R 激活，并在小动脉测定中诱导血管收缩，这两种情况均被氯沙坦和 RID 肽阻断。对免疫兔进行单次静脉推注 RID 肽 (1 mg/kg)，平均动脉压从 122±11 mmHg 降至 82±6 mmHg。兔抗 AT1R 血清部分抑制了血管紧张素 II 诱导的离体大鼠提睾小动脉的收缩，并且在免疫动物中对血管紧张素 II 输注的升压反应减弱。总之，AT1R 激活自身抗体和 RID 肽分别对携带这些自身抗体的高血压受试者具有重要的病因学和治疗意义。
Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been implicated in hypertensive disorders. We investigated whether AT1R antibodies produced in immunized rabbits will activate AT1R and contribute to hypertension by a direct contractile effect on the vasculature; and if they can be blocked by a novel decoy peptide. A multiple antigenic peptide containing the AT1R epitope AFHYESQ, which is the receptor binding epitope of AT1R-activating autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was analyzed in AT1R-transfected cells, and their contractile effects were assayed using isolated perfused rat cremaster resistance arterioles. A retro-inverso D-amino acid (RID) epitope-mimetic peptide was tested for AT1R antibody inhibition in vitro and in vivo. All immunized animals produced high AT1R antibody titers and developed elevated blood pressure. No changes in measured blood chemistry values were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R activation in transfected cells and vasoconstriction in the arteriole assay, both of which were blocked by losartan and the RID peptide. A single intravenous bolus injection of the RID peptide (1 mg/kg) into immunized rabbits dropped the mean arterial pressure from 122±11 mmHg to 82±6 mmHg. Rabbit anti-AT1R sera partially suppressed angiotensin II-induced contraction of isolated rat cremaster arterioles, and the pressor response to angiotensin II infusion was attenuated in immunized animals. In conclusion, AT1R-activating autoantibodies and the RID peptide respectively have important etiological and therapeutic implications in hypertensive subjects who harbor these autoantibodies.