Zhou Jin, Pavel Jaroslav, Macova Miroslava, Yu Zu-Xi, Imboden Hans, Ge Linna, Nishioku Tsuyoshi, Dou Jingtao, Delgiacco Elizabeth, Saavedra Juan M
Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Stroke. 2006 May;37(5):1271-6. doi: 10.1161/01.STR.0000217404.64352.d7. Epub 2006 Apr 6.
Blockade of angiotensin II AT1 receptors in cerebral microvessels protects against brain ischemia and inflammation. In this study, we tried to clarify the presence and regulation of the local renin-angiotensin system (RAS) in brain microvessels in hypertension.
Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls were treated with an AT1 receptor antagonist (candesartan, 0.3 mg/kg per day) via subcutaneous osmotic minipumps for 4 weeks. The expression and localization of RAS components and the effect of AT1 receptor blockade were assessed by Affymetrix microarray, qRT-PCR, Western blots, immunohistochemistry and immunofluorescence.
We found transcripts of most of RAS components in our microarray database, and confirmed their expression by qRT-PCR. Angiotensinogen (Aogen), angiotensin-converting enzyme (ACE) and AT1 receptors were localized to the endothelium. There was no evidence of AT2 receptor localization in the microvascular endothelium. In SHR, (pro)renin receptor mRNA and AT1 receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT2 receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT2 receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro)renin and AT1 receptors.
Increased (pro)renin and AT1 receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT1 receptor blockade and increased AT2 receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.
阻断脑微血管中的血管紧张素II 1型受体（AT1受体）可预防脑缺血和炎症。在本研究中，我们试图阐明高血压状态下脑微血管中局部肾素-血管紧张素系统（RAS）的存在情况及调控机制。
通过皮下渗透微型泵，对自发性高血压大鼠（SHR）和Wistar Kyoto（WKY）对照大鼠给予AT1受体拮抗剂（坎地沙坦，每天0.3mg/kg），持续4周。采用Affymetrix微阵列、定量逆转录聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法、免疫组织化学和免疫荧光法评估RAS组分的表达与定位以及AT1受体阻断的效果。
我们在微阵列数据库中发现了大多数RAS组分的转录本，并通过qRT-PCR证实了它们的表达。血管紧张素原（Aogen）、血管紧张素转换酶（ACE）和AT1受体定位于内皮细胞。没有证据表明微血管内皮细胞中有AT2受体定位。在SHR中，（前）肾素受体mRNA以及AT1受体mRNA和蛋白表达较高，而Aogen、ACE mRNA以及AT2受体mRNA和蛋白表达低于WKY大鼠。坎地沙坦治疗使SHR中的Aogen、ACE和AT2受体增加，使WKY大鼠中的ACE增加而Aogen减少，且不影响（前）肾素和AT1受体。
SHR中（前）肾素和AT1受体表达增加，证实了局部RAS过度激活在高血压脑血管病理生理学中的重要性。坎地沙坦给药后，AT1受体阻断及AT2受体刺激增加可能有助于预防脑缺血和炎症。
Zotero 插件