Effect of olmesartan on tissue expression balance between angiotensin II receptor and its inhibitory binding molecule
Effect of olmesartan on tissue expression balance between angiotensin II receptor and its inhibitory binding molecule
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DOI：
10.1161/hypertensionaha.108.117341
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发表时间：
2008-10-01
期刊：
影响因子：
8.3
通讯作者：
Umemura, Satoshi
中科院分区：
文献类型：
--
作者：
Shigenaga, Atsu-ichiro;Tamura, Kouichi;Umemura, Satoshi
我们先前克隆了一种与血管紧张素II（Ang II）1型受体蛋白（ATRAP）相互作用的新型分子，并表明它是心血管细胞中Ang II 1型受体信号传导的内源性抑制剂。在本研究中，我们检验了一个假设，即在高血压及相关心肌肥大的发展过程中，ATRAP和Ang II 1型受体的组织表达平衡是以组织特异性的方式进行调节的。在自发性高血压大鼠中，随着血压升高和心肌肥大，心脏中ATRAP与Ang II 1型受体表达的比值出现持续性下降。然而，用奥美沙坦（一种Ang II 1型受体特异性拮抗剂）治疗，无论是降压剂量还是亚降压剂量，都能使被抑制的心脏ATRAP与Ang II 1型受体的比值恢复，同时伴有Ang II 1型受体密度降低、p38丝裂原活化蛋白激酶活性受抑制以及心肌肥大消退。此外，Ang II刺激在心肌细胞和大鼠心脏中均抑制了ATRAP与Ang II 1型受体的比值，并伴有肥大反应。这些发现表明，在高血压和心脏重构的发展过程中，ATRAP和Ang II 1型受体的表达存在组织特异性的调节平衡，并且进一步提示，组织中ATRAP与Ang II 1型受体比值的上调可能是奥美沙坦除降压作用之外的治疗益处之一。
We previously cloned a novel molecule interacting with angiotensin II (Ang II) type 1 receptor protein (ATRAP) and showed it to be an endogenous inhibitor of Ang II type 1 receptor signaling in cardiovascular cells. In this study, we tested a hypothesis that the balance of tissue expression of ATRAP and Ang II type 1 receptor is regulated in a tissue-specific manner during the development of hypertension and related cardiac hypertrophy. Concomitant with blood pressure increase and cardiac hypertrophy in spontaneously hypertensive rats, there was a constitutive decrease in the ratio of cardiac expression of ATRAP to Ang II type 1 receptor. However, treatment with olmesartan, an Ang II type 1 receptor-specific antagonist, either at a depressor or subdepressor dose, recovered the suppressed cardiac ATRAP to Ang II type 1 receptor ratio, which was accompanied by a decrease in Ang II type 1 receptor density, an inhibition of p38 mitogen-activated protein kinase activity, and a regression of cardiac hypertrophy. Furthermore, Ang II stimulation suppressed the ATRAP to Ang II type 1 receptor ratio with hypertrophic responses in both the cardiomyocytes and rat hearts. These findings show a tissue-specific regulatory balancing of the expression of ATRAP and Ang II type 1 receptor during the development of hypertension and cardiac remodeling and further suggest that the upregulation of the tissue ATRAP to Ang II type 1 receptor ratio may be one of the therapeutic benefits of olmesartan beyond its blood pressure-lowering effect.