Document Detail

Mitochondrial dysfunction in the hypertensive rat brain: respiratory complexes exhibit assembly defects in hypertension.
MedLine Citation:
PMID:  18172056     Owner:  NLM     Status:  MEDLINE    
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.
Ana Lopez-Campistrous; Li Hao; Wang Xiang; Dong Ton; Paul Semchuk; Joerg Sander; Michael J Ellison; Carlos Fernandez-Patron
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-01-02
Journal Detail:
Title:  Hypertension     Volume:  51     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-24     Completed Date:  2008-02-26     Revised Date:  2014-02-07    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  412-9     Citation Subset:  IM    
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MeSH Terms
Brain / enzymology*
Cardiovascular System / physiopathology
Doxycycline / pharmacology
Electrophoresis, Gel, Two-Dimensional
Enzyme Inhibitors / pharmacology
Hypertension / complications*,  enzymology,  physiopathology*
Metalloendopeptidases / antagonists & inhibitors
Mitochondrial Diseases / enzymology,  etiology*
Multienzyme Complexes / drug effects,  genetics*
Protein Processing, Post-Translational* / drug effects
Rats, Inbred SHR
Rats, Inbred WKY
Tandem Mass Spectrometry
Grant Support
62718-1//Canadian Institutes of Health Research
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Multienzyme Complexes; EC 3.4.24.-/Metalloendopeptidases; N12000U13O/Doxycycline

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