Kato Norihiro, Liang Yi-Qiang, Ochiai Yoshinori, Birukawa Naoko, Serizawa Masakuni, Jesmin Subrina
Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan. Tokyo, Japan.
Hypertens Res. 2008 Oct;31(10):1963-75. doi: 10.1291/hypres.31.1963.
To test the functional consequences of blocking the local renin-angiotensin system (RAS), we investigated the effects of an angiotensin II type 1 receptor blocker (ARB), candesartan, on the systemic gene expression profile of five important organs (brain, heart, kidney, liver and adipose tissues) in the stroke-prone spontaneously hypertensive rat (SHRSP), an established model of essential hypertension and cardiovascular disorders, and its normotensive control, the Wistar Kyoto (WKY) rat. Rats were treated with candesartan (5 mg/kg/d) for 4 weeks from 12 to 16 weeks of age. DNA microarray technology was used to identify changes in gene expression. Four weeks of treatment with candesartan significantly lowered systolic blood pressure in male rats of both the SHRSP and the WKY strains (p<0.0005). Candesartan differentially modulated the gene expression profile in an organ-specific manner in male SHRSP; of the five organs tested, gene expression was most prominently altered in the hearts of SHRSP. In contrast, candesartan treatment exerted minimal or no significant effects on the gene expression profile of the corresponding organs of male WKY rats. The inter-strain differences in gene expression changes induced by candesartan were considered to be associated with both blood pressure-dependent and independent mechanisms. These results help to delineate the mechanisms that underlie the organ or tissue protection conferred by ARB at the levels of cellular biology and genomics in the context of the local RAS. Further studies are warranted to investigate not only individual genes of interest but also genetic "networks" that involve differential organ- or tissue-specific gene expression induced by the blockade of RAS in essential hypertension. Tokyo, Japan
为了测试阻断局部肾素-血管紧张素系统（RAS）的功能后果，我们研究了血管紧张素II 1型受体阻滞剂（ARB）坎地沙坦对易患中风的自发性高血压大鼠（SHRSP）（一种已确立的原发性高血压和心血管疾病模型）及其血压正常的对照Wistar Kyoto（WKY）大鼠五个重要器官（脑、心脏、肾脏、肝脏和脂肪组织）的全身基因表达谱的影响。大鼠在12至16周龄时接受坎地沙坦（5 mg/kg/d）治疗4周。使用DNA微阵列技术来识别基因表达的变化。坎地沙坦治疗4周可显著降低SHRSP和WKY品系雄性大鼠的收缩压（p<0.0005）。坎地沙坦以器官特异性方式差异性地调节雄性SHRSP的基因表达谱；在所测试的五个器官中，SHRSP心脏中的基因表达变化最为显著。相比之下，坎地沙坦治疗对雄性WKY大鼠相应器官的基因表达谱影响极小或无显著影响。坎地沙坦诱导的基因表达变化的品系间差异被认为与血压依赖性和非依赖性机制均有关。这些结果有助于在局部RAS的背景下，在细胞生物学和基因组学水平上阐明ARB赋予器官或组织保护的潜在机制。不仅有必要进一步研究感兴趣的单个基因，而且还有必要研究涉及原发性高血压中RAS阻断诱导的差异性器官或组织特异性基因表达的遗传“网络”。日本东京
