NOX1 deficiency protects from aortic dissection in response to angiotensin II
NOX1 deficiency protects from aortic dissection in response to angiotensin II
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DOI：
10.1161/hypertensionaha.107.089706
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发表时间：
2007-07-01
期刊：
影响因子：
8.3
通讯作者：
Krause, Karl-Heinz
中科院分区：
文献类型：
--
作者：
Gavazzi, Gaetan;Deffert, Christine;Krause, Karl-Heinz
氧化应激导致血管损伤，并参与主动脉夹层和动脉瘤形成的病理机制。在这里，我们研究了小鼠的主动脉夹层，这些小鼠缺乏产生超氧化物的还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶NOX 1。用高血压药物血管紧张素II（每天3 mg/kg）治疗7天，导致23%的野生型C57 BL/6 J小鼠发生主动脉夹层，但仅4%的NOX 1缺陷小鼠发生主动脉夹层（P = 0.05）。相比之下，用高血压药物去甲肾上腺素（12 mg/kg/天）治疗野生型C57 BL/6 J小鼠，未导致主动脉夹层或猝死，表明高血压不足以引起主动脉夹层。有趣的是，去甲肾上腺素依赖性血压升高在NOX 1缺陷小鼠中是保守的，这表明与血管紧张素II不同，它通过NOX 1非依赖性高血压机制起作用。NOX 1缺陷小鼠对血管紧张素II诱导的主动脉夹层的抵抗表明血管壁的NOX 1依赖性改变的作用。因此，我们研究了基因表达和蛋白酶/抑制剂平衡。cDNA阵列分析表明血管紧张素II对野生型和NOX 1缺陷小鼠基因表达的差异作用。在NOX 1缺陷小鼠中，基质金属蛋白酶组织抑制因子1在mRNA和蛋白水平上均增加。因此，我们的研究结果表明，NOX 1参与血管紧张素II依赖性主动脉夹层的机制。作为一个潜在的机制，我们已经确定了NOX 1依赖性抑制金属蛋白酶1表达的组织抑制剂，这可能会导致组织损伤，通过改变蛋白酶/抑制剂平衡。
Oxidative stress leads to vascular damage and participates in the pathomechanisms of aortic dissection and aneurysm formation. Here we study aortic dissection in mice deficient in the superoxide-generating reduced nicotinamide-adenine dinucleotide phosphate oxidase NOX1. Seven days of treatment with the hypertensive agent angiotensin II (3 mg/kg per day) led to aortic dissection in 23% of wild-type C57BL/6J mice but in only 4% of NOX1-deficient mice (P = 0.05). In contrast, treatment of wild-type C57BL/6J mice with the hypertensive agent norepinephrine (12 mg/kg per day), did not lead to aortic dissection or sudden death, suggesting that hypertension is not sufficient to cause aortic dissection. Interestingly, norepinephrine-dependent blood pressure elevations were conserved in NOX1-deficient mice, demonstrating that, different from angiotensin II, it acts through NOX1-independent hypertensive mechanisms. The resistance of NOX1-deficient mice to angiotensin II - induced aortic dissection suggests a role for NOX1-dependent alterations of the vascular wall. We, therefore, studied gene expression and protease/inhibitor equilibrium. cDNA array analysis demonstrated differential effects of angiotensin II on gene expression in wild-type and NOX1-deficient mice. Tissue inhibitor of metalloproteinase 1 was increased both on the mRNA and the protein level in aortas from NOX1-deficient mice. Thus, our results demonstrate that NOX1 is involved in the mechanisms of angiotensin II - dependent aortic dissection. As one underlying mechanism, we have identified NOX1- dependent suppression of tissue inhibitor of metalloproteinase 1 expression, which could lead to tissue damage through an altered protease/inhibitor balance.