The Role of Cytochrome P-450 in Salt-Sensitive Stroke in Stroke-Prone Spontaneously Hypertensive Rats
The Role of Cytochrome P-450 in Salt-Sensitive Stroke in Stroke-Prone Spontaneously Hypertensive Rats
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DOI：
10.1291/hypres.31.1821
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发表时间：
2008-09
影响因子：
5.4
通讯作者：
Chen-Jiang Ying;T. Noguchi;H. Aso;K. Ikeda;Y. Yamori;Y. Nara
中科院分区：
文献类型：
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作者：
Chen-Jiang Ying;T. Noguchi;H. Aso;K. Ikeda;Y. Yamori;Y. Nara
卒中易感自发性高血压大鼠（SHRSP/Izm）对盐敏感，在盐负荷后短时间内发生严重高血压并死于中风。我们研究了细胞色素P-450（CYP）亚型在脑中的作用和氯贝特的作用，以探讨SHRSP/Izm患者盐敏感卒中倾向的机制。9周龄雄性SHRSP/Izm分别饲喂添加或不添加0.25%氯贝酸盐的常规饲料，并给予1% NaCl溶液作为饮用水，持续10 d。采用Western blotting检测CYP4A1、2C11和2C23的表达水平。用激光多普勒法测量脑血流，显微镜下测量血管直径。SHRSP/Izm在盐加载后60 d内死亡；然而，氯贝特延长了生存期（平均寿命，33±7天和215±23天，p<0.0001），但没有显著降低严重高血压。与同龄雄性自发性高血压大鼠（SHR/Izm）相比，SHRSP/Izm组大脑皮层CYP4A1、CYP2C11表达水平明显降低（p<0.05）。SHRSP/Izm组和SHR/Izm组均未观察到脑组织CYP4A1的明显变化。氯贝特显著上调大脑CYP2C11的表达，显著减弱其盐诱导的抑制作用（p<0.05）。此外，氯贝特显著增加血管直径（p<0.01）和脑血流量（p<0.0001）。CYP2C11在调节脑血流中起重要作用，因此在盐敏感卒中易发的SHRSP/Izm中预防卒中。
Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) are salt sensitive: they develop severe hypertension and die of stroke within a short time after salt loading. We studied the role of cytochrome P-450(CYP) isoforms in the brain and the effect of clofibrate to investigate the mechanism of salt sensitive stroke-proneness in SHRSP/Izm. Male SHRSP/Izm at 9 weeks of age were fed a regular diet with or without 0.25% clofibrate and given a 1% NaCl solution for drinking water for 10 d. The expression levels of CYP4A1, 2C11, and 2C23 were measured by Western blotting. Cerebral blood flow was measured with a laser Doppler method and blood vessel diameters were measured under microscopic observation. SHRSP/Izm died within 60 d after salt loading; however, clofibrate prolonged the survival (mean life span, 33±7 vs. 215±23 d, p<0.0001) without significant attenuation of the severe hypertension. CYP4A1 and CYP2C11 expression levels were lower in SHRSP/Izm than those in age-matched male spontaneously hypertensive rats (SHR/Izm) in the cerebral cortex of SHRSP/Izm (p<0.05). No obvious change in cerebral CYP4A1 was observed in either salt-loaded SHRSP/Izm or SHR/Izm. Clofibrate significantly up-regulated the expression of cerebral CYP2C11 and significantly attenuated its salt-induced suppression (p<0.05). Additionally, clofibrate significantly increased blood vessel diameters (p<0.01) and cerebral blood flow (p<0.0001). CYP2C11 plays an important role in regulating cerebral blood flow and, as a result, in preventing stroke in the salt-sensitive stroke-prone SHRSP/Izm.