Mitochondrial dysfunction in the hypertensive rat brain - Respiratory complexes exhibit assembly defects in hypertension
Mitochondrial dysfunction in the hypertensive rat brain - Respiratory complexes exhibit assembly defects in hypertension
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DOI：
10.1161/hypertensionaha.107.102285
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发表时间：
2008-02-01
期刊：
影响因子：
8.3
通讯作者：
Fernandez-Patron, Carlos
中科院分区：
文献类型：
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作者：
Lopez-Campistrous, Ana;Hao, Li;Fernandez-Patron, Carlos
中枢神经系统在动脉血压的正常控制和几乎所有形式的高血压的升高中起关键作用。线粒体功能障碍已越来越多地与高血压的发展相关。因此，我们研究了线粒体功能障碍是否发生在高血压的大脑中，并在分子水平上进行了表征。将12周龄自发性高血压大鼠血压升高（190+/-5 mm Hg）的全脑和脑干的线粒体与年龄匹配的正常血压（134+/-7 mm Hg）Wistar京都大鼠的线粒体进行比较（每组n=4）。使用二维电泳的全球差异分析，然后基于串联质谱的蛋白质鉴定表明，参与高血压细胞能量学的酶下调。有针对性的差异分析线粒体呼吸复合物使用经典的蓝色-天然SDS-PAGE/Western方法和蔗糖梯度超离心/串联质谱的互补组合揭示了以前未知的组装缺陷的复合物I，III，IV和V的高血压。有趣的是，对脑干（心血管稳态和全身血压的调节器）的靶向检查进一步显示了高血压中线粒体复合物I功能障碍、活性氧产生增加、ATP合成减少和呼吸受损的发生。我们的研究结果表明，在已经高血压的自发性高血压大鼠，脑呼吸复合体表现出以前未知的组装缺陷。这些缺陷损害线粒体呼吸链的功能。这种线粒体功能障碍局限于脑干，因此可能有助于高血压的发展以及病理生理并发症。
The central nervous system plays a critical role in the normal control of arterial blood pressure and in its elevation in virtually all forms of hypertension. Mitochondrial dysfunction has been increasingly associated with the development of hypertension. Therefore, we examined whether mitochondrial dysfunction occurs in the brain in hypertension and characterized it at the molecular scale. Mitochondria from whole brain and brain stem from 12-week-old spontaneously hypertensive rats with elevated blood pressure (190+/-5 mm Hg) were compared against those from age-matched normotensive (134+/-7 mm Hg) Wistar Kyoto rats (n=4 in each group). Global differential analysis using 2D electrophoresis followed by tandem mass spectrometry-based protein identification suggested a downregulation of enzymes involved in cellular energetics in hypertension. Targeted differential analysis of mitochondrial respiratory complexes using the classical blue-native SDS-PAGE/Western method and a complementary combination of sucrose-gradient ultracentrifugation/tandem mass spectrometry revealed previously unknown assembly defects in complexes I, III, IV, and V in hypertension. Interestingly, targeted examination of the brain stem, a regulator of cardiovascular homeostasis and systemic blood pressure, further showed the occurrence of mitochondrial complex I dysfunction, elevated reactive oxygen species production, decreased ATP synthesis, and impaired respiration in hypertension. Our findings suggest that in already-hypertensive spontaneously hypertensive rats, the brain respiratory complexes exhibit previously unknown assembly defects. These defects impair the function of the mitochondrial respiratory chain. This mitochondrial dysfunction localizes to the brain stem and is, therefore, likely to contribute to the development, as well as to pathophysiological complications, of hypertension.