An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat
An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat
复制标题
DOI：
10.1152/ajpheart.00870.2006
复制
发表时间：
2007-07-01
影响因子：
4.8
通讯作者：
Katusic, Zvonimir S.
中科院分区：
文献类型：
--
作者：
Nath, Karl A.;d'Uscio, Livius V.;Katusic, Zvonimir S.
doca -盐模型高血压大鼠血管中血红素加氧酶-1 （HO-1）的表达。尽管HO系统及其产物可能发挥血管舒张作用，但最近的研究表明，HO系统可能易患高血压。本研究考察了HO系统的选定组分，特别是HO-1同工酶和产物胆红素在全体性高血压doca -盐模型中的作用；实验方法采用突变鼠模型，即HO-1（-/-）小鼠和高胆红素血症的Gunn大鼠。doca盐诱导HO-1（-/-）小鼠主动脉HO-1蛋白表达，并引起HO-1（-/-）小鼠动脉收缩压显著升高，但HO-1（-/-）小鼠无明显升高；这种影响不能归因于doca盐处理HO-1（-/-）小鼠尿钠排泄受损或肾小球滤过率受损。未去肾大鼠给药DOCA盐显著增加野生型大鼠的收缩压，在突变型Gunn大鼠中这种作用减弱；在doca盐处理的Gunn大鼠中，这种全身性高血压的减少不是由于血管中HO-1的更大诱导或更强烈的尿钠排泄。DOCA-salt对野生型大鼠内皮依赖性和内皮非依赖性血管松弛的影响，而对Gunn大鼠没有影响；先前暴露于胆红素可修复doca盐处理大鼠主动脉环内皮依赖性血管松弛缺陷。DOCA盐刺激野生型大鼠血管产生超氧阴离子，但对Gunn大鼠无刺激作用。我们认为HO-1及其产物胆红素可能在doca -盐模型的全身性高血压中发挥抵消作用。
Heme oxygenase-1 (HO-1) is induced in the vasculature in the DOCA-salt model of hypertension in rats. Whereas the HO system and its products may exert vasodilator effects, recent studies have suggested that the HO system may predispose to hypertension. The present study examined the effects of selected components of the HO system, specifically, the HO-1 isozyme and the product bilirubin in the DOCA-salt model of systemic hypertension; the experimental approach employed mutant rodent models, namely, the HO-1(-/-) mouse and the hyperbilirubinemic Gunn rat. DOCA-salt induced HO-1 protein in the aorta in HO-1(-/-) mice and provoked a significant rise in systolic arterial pressure in HO-1(-/-) mice but not in HO-1(-/-) mice; this effect could not be ascribed to impaired urinary sodium excretion or impaired glomerular filtration rate in the DOCA-salt-treated HO-1(-/-) mice. The administration of DOCA salt to uninephrectomized rats significantly increased systolic arterial pressure in wild-type rats, an effect that was attenuated in the mutant Gunn rat; this reduction in systemic hypertension in the DOCA-salt-treated Gunn rat was not due to a greater induction of HO-1 in the vasculature or to a more avid urinary sodium excretion. DOCA-salt impaired endothelium-dependent and endothelium-independent vasorelaxation in wild-type rats but not in Gunn rats; prior exposure to bilirubin repaired the defect in endothelium-dependent vasorelaxation in aortic rings in DOCA-salt-treated rats. DOCA salt stimulated vascular production of superoxide anion in wild-type but not in Gunn rats. We suggest that HO-1 and the product bilirubin may exert a countervailing effect in the DOCA-salt model of systemic hypertension.