Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension
Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension
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DOI：
10.1161/hypertensionaha.108.116905
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发表时间：
2009-02-01
期刊：
影响因子：
8.3
通讯作者：
Chan, Julie Y. H.
中科院分区：
文献类型：
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作者：
Chan, Samuel H. H.;Wu, Kay L. H.;Chan, Julie Y. H.
线粒体电子传递链（ETC）在神经源性高血压中的作用尚不清楚。我们评估了超氧阴离子（O-2（中心点-））和过氧化氢（H2O2）在延髓吻侧腹外侧（RVLM）前反馈抑制线粒体ETC功能的假设，RVLM是维持交感血管舒张性的脑干部位，参与氧化应激和高血压的神经机制。与正常Wistar-Kyoto大鼠相比，自发性高血压大鼠在RVLM中表现出线粒体ETC功能障碍，表现为复合物I或III活性降低，复合物I与III或II与III之间的电子偶联能力降低。在自发性高血压大鼠RVLM中微量注射辅酶Q（10）可逆转ETC活性降低、O-2（中心点-）生成增加和高血压表型。这种移动电子载体还可以拮抗RVLM中升高的H2O2，以及Wistar-Kyoto或高血压前期大鼠对复合物I（鱼藤酮）或III（抗霉素A）抑制剂的血管加压反应。脑室内灌注血管紧张素II可促进Wistar-Kyoto大鼠线粒体ETC功能障碍，辅酶Q（10）或NADPH氧化酶p22（phox）亚基基因敲低可拮抗RVLM中H2O2的升高。通过基因转移在自发性高血压大鼠RVLM中过表达超氧化物歧化酶或过氧化氢酶，可逆转线粒体功能障碍，使RVLM中增加的O-2（中心点-）和H2O2钝化。我们得出结论，由于超氧化物歧化酶或过氧化氢酶的易感性下调以及NADPH氧化酶衍生的O-2（中心点-）和ETC酶之间的交叉对话导致自发性高血压大鼠RVLM中的慢性氧化应激，导致交感血管舒张性增强和高血压。[中国高血压杂志];2009;53:217-227.]
The role for mitochondrial electron transport chain (ETC) in neurogenic hypertension is unidentified. We evaluated the hypothesis that feedforward depression of mitochondrial ETC functions by superoxide anion (O-2(center dot-)) and hydrogen peroxide (H2O2) in rostral ventrolateral medulla (RVLM), a brain stem site that maintains sympathetic vasomotor tone and contributes to oxidative stress and neural mechanism of hypertension. Compared with normotensive Wistar-Kyoto rats, spontaneously hypertensive rats exhibited mitochondrial ETC dysfunctions in RVLM in the forms of depressed complex I or III activity and reduced electron coupling capacity between complexes I and III or II and III. Microinjection of coenzyme Q(10) into RVLM of spontaneously hypertensive rats reversed the depressed ETC activity and augmented O-2(center dot-) production and hypertensive phenotypes. This mobile electron carrier also antagonized the elevated H2O2 in RVLM and vasopressor responses to complex I (rotenone) or III (antimycin A) inhibitor in Wistar-Kyoto or prehypertensive rats. Intracerebroventricular infusion of angiotensin II promoted mitochondrial ETC dysfunctions in Wistar-Kyoto rats, and coenzyme Q(10) or gene knockdown of the p22(phox) subunit of NADPH oxidase antagonized the resultant elevation of H2O2 in RVLM. Overexpression of superoxide dismutase or catalase in RVLM of spontaneously hypertensive rats by gene transfer reversed mitochondrial dysfunctions and blunted the augmented O-2(center dot-) and H2O2 in RVLM. We conclude that O-2(center dot-) - and H2O2-dependent feedforward impairment of mitochondrial ETC complexes because of predisposed downregulation of superoxide dismutase or catalase and a cross-talk between NADPH oxidase-derived O-2(center dot-) and ETC enzymes contribute to chronic oxidative stress in the RVLM of spontaneously hypertensive rats, leading to augmented sympathetic vasomotor tone and hypertension. (Hypertension. 2009; 53: 217-227.)