Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals
Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals
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1 型血管紧张素 II 受体治疗疫苗在高血压动物中的有效性和安全性
DOI：
10.1161/hypertensionaha.112.201020
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发表时间：
2013-02-01
期刊：
影响因子：
8.3
通讯作者：
Liao, Yuhua
中科院分区：
文献类型：
--
作者：
Chen, Xiao;Qiu, Zhihua;Liao, Yuhua
原发性高血压是一种发病率较高的慢性病，世界范围内的血压控制率远不能令人满意。接种疫苗为治疗高血压和改善依从性提供了一种很有前途的方法。在这里，ATRQβ-001疫苗，一种来源于人血管紧张素II(Ang II)受体1型与Qβ噬菌体病毒样颗粒结合的多肽(ATR-001)，被开发出来并在高血压动物模型中进行了评估。ATRQβ-001疫苗可显著降低血管紧张素转换酶诱导的高血压小鼠的血压至35 mm Hg(143±/-4vs178+/-6 mm Hg；P=0.005)和自发性高血压大鼠至19 mm Hg的血压(173+/-2 vs192+/-3 mm Hg；P=0.003)，并阻止脆弱的高血压靶器官的重建。未观察到循环或局部肾素-血管紧张素系统的反馈激活。此外，在接种疫苗的高血压和非高血压动物中没有检测到显著的免疫介导的损害。抗ATR-001抗体的半衰期为14.4天，超过现有化学药物。在体外，抗ATR001抗体可与血管紧张素Ⅱ1型受体特异性结合并抑制钙依赖的信号转导活动，包括蛋白激酶C-α易位、细胞外信号调节激酶1/2磷酸化(降低72%；P=0.013)和血管紧张素Ⅱ诱导的细胞内钙升高(降低68%；P=0.017)，但不抑制血管紧张素Ⅱ与受体的结合。综上所述，ATRQβ-001疫苗通过降低血管紧张素Ⅱ诱导的血压反应，抑制血管紧张素Ⅱ诱导的信号转导，有效地降低了血管紧张素Ⅱ诱导的高血压小鼠和自发性高血压大鼠的血压，为治疗原发性高血压提供了一种新的、有前途的方法。(高血压。2013；61：408-416。)圆圈在线数据补充
Primary hypertension is a chronic disease with high morbidity, and the rate of controlled blood pressure is far from satisfactory, worldwide. Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. Here, the ATRQ beta-001 vaccine, a peptide (ATR-001) derived from human angiotensin II (Ang II) receptor type 1 conjugated with Q beta bacteriophage virus-like particles, was developed and evaluated in animal models of hypertension. The ATRQ beta-001 vaccine significantly decreased the blood pressure of Ang II-induced hypertensive mice up to 35 mm Hg (143 +/- 4 versus 178 +/- 6 mm Hg; P=0.005) and that of spontaneously hypertensive rats up to 19 mm Hg (173 +/- 2 versus 192 +/- 3 mm Hg; P=0.003) and prevented remodeling of vulnerable hypertensive target organs. No obvious feedback activation of circulating or local renin-angiotensin system was observed. Additionally, no significant immune-mediated damage was detected in vaccinated hypertensive and nonhypertensive animals. The half-life of the anti-ATR-001 antibody was 14.4 days, surpassing that of existing chemical drugs. In vitro, the anti-ATR-001 antibody specifically bound to Ang II receptor type 1 and inhibited Ca2+-dependent signal transduction events, including protein kinase C-alpha translocation, extracellular signal- regulated kinase 1/2 phosphorylation (72% decrease; P=0.013), and elevation of intracellular Ca2+ (68% decrease; P=0.017) induced by Ang II, but without inhibiting Ang II binding to the receptor. In conclusion, the ATRQ beta-001 vaccine decreased the blood pressure of Ang II-induced hypertensive mice and spontaneously hypertensive rats effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II. Thus, the ATRQ beta-001 vaccine may provide a novel and promising method for the treatment of primary hypertension. (Hypertension. 2013;61:408-416.) circle Online Data Supplement