Suvorava Tatsiana, Lauer Nadine, Kumpf Stephanie, Jacob Ralf, Meyer Wilfried, Kojda Georg
Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
Circulation. 2005 Oct 18;112(16):2487-95. doi: 10.1161/CIRCULATIONAHA.105.543157. Epub 2005 Oct 10.
Although many studies suggested direct vasomotor effects of hydrogen peroxide (H2O2) in vitro, little is known about the vasomotor effects of H2O2 in vivo.
We have generated mice overexpressing human catalase driven by the Tie-2 promoter to specifically target this transgene to the vascular tissue. Vessels of these mice (cat++) expressed significantly higher levels of catalase mRNA, protein, and activity. The overexpression was selective for vascular tissue, as evidenced by immunohistochemistry in specimens of aorta, heart, lung, and kidney. Quantification of reactive oxygen species by fluorescence signals in cat++ versus catalase-negative (catn) mice showed a strong decrease in aortic endothelium and left ventricular myocardium but not in leukocytes. Awake male cat++ at 3 to 4 months of age had a significantly lower systolic blood pressure (sBP, 102.7+/-2.2 mm Hg, n=10) compared with their transgene-negative littermates (catn, 115.6+/-2.5 mm Hg, P=0.0211) and C57BL/6 mice (118.4+/-3.06 mm Hg, n=6). Treatment with the catalase inhibitor aminotriazole increased sBP of cat++ to 117.3+/-4.3 mm Hg (P=0.0345), while having no effect in catn (118.4+/-2.4 mm Hg, n=4, P>0.05). In contrast, treatment with the NO-synthase inhibitor nitro-L-arginine methyl ester (100 mg.kg BW(-1).d(-1)) increased sBP in cat++ and C57Bl/6 to a similar extent. Likewise, phosphorylation of vasodilator-stimulated phosphoprotein in skeletal muscle, left ventricular myocardium, and lung was identical in cat++ and catn. Endothelium- and NO-dependent aortic vasodilations were unchanged in cat++. Aortic KCl contractions were significantly lower in cat++ and exogenous H2O2 (10 micromol/L)-induced vasoconstriction.
These data suggest that endogenous H2O2 may act as a vasoconstrictor in resistance vessels and contribute to the regulation of blood pressure.
尽管许多研究表明过氧化氢（H2O2）在体外具有直接的血管舒缩作用，但关于H2O2在体内的血管舒缩作用却知之甚少。
我们构建了由Tie-2启动子驱动的过表达人过氧化氢酶的小鼠，以使该转基因特异性靶向血管组织。这些小鼠（cat++）的血管中过氧化氢酶mRNA、蛋白质和活性水平显著更高。过表达对血管组织具有选择性，主动脉、心脏、肺和肾脏标本的免疫组织化学结果证明了这一点。通过荧光信号对cat++小鼠与过氧化氢酶阴性（catn）小鼠中的活性氧进行定量分析，结果显示主动脉内皮和左心室心肌中的活性氧显著减少，但白细胞中没有。3至4月龄的清醒雄性cat++小鼠的收缩压（sBP，102.7±2.2 mmHg，n = 10）显著低于其转基因阴性同窝小鼠（catn，115.6±2.5 mmHg，P = 0.0211）和C57BL/6小鼠（118.4±3.06 mmHg，n = 6）。用过氧化氢酶抑制剂氨基三唑处理可使cat++小鼠的sBP升高至117.3±4.3 mmHg（P = 0.0345），而对catn小鼠没有影响（118.4±2.4 mmHg，n = 4，P>0.05）。相反，用一氧化氮合酶抑制剂硝基-L-精氨酸甲酯（100 mg·kg BW-1·d-1）处理可使cat++小鼠和C57Bl/6小鼠的sBP升高至相似程度。同样，cat++小鼠和catn小鼠骨骼肌、左心室心肌和肺中血管舒张刺激磷蛋白的磷酸化情况相同。cat++小鼠中内皮依赖性和一氧化氮依赖性主动脉舒张未发生变化。cat++小鼠的主动脉氯化钾收缩以及外源性H2O2（10 μmol/L）诱导的血管收缩显著降低。
这些数据表明内源性H2O2可能在阻力血管中作为血管收缩剂起作用，并有助于血压调节。
