Published online before print January 2, 2008, doi: 10.1161/HYPERTENSIONAHA.107.102285
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(Hypertension. 2008;51:412.)
© 2008 American Heart Association, Inc.
Original Articles |
Mitochondrial Dysfunction in the Hypertensive Rat Brain
Respiratory Complexes Exhibit Assembly Defects in Hypertension
From the Department of Biochemistry (A.L.-C., L.H., W.X., D.T., P.S., M.J.E., C.F.-P.), Institute for Biomolecular Design (A.L.-C., P.S., M.J.E.), and Department of Computing Science (J.S.), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Carlos Fernandez-Patron, University of Alberta, 3-19 Medical Sciences, Edmonton, Alberta, T6G 2H7 Canada. E-mail carlos.fernandez-patron{at}ualberta.ca
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Abstract |
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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.
Key Words: hypertension • mitochondria • proteomics • brain • oxidative stress
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Introduction |
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Hypertension (the state characterized by sustained high blood pressure) remains a poorly understood, multifactorial condition affecting >25% of the adult population in developed countries. It is a major risk factor for heart and peripheral vascular disease, as well as cerebral stroke.1 An emerging common hallmark of many cardiovascular conditions, including hypertension, is the dysfunction of mitochondria.2–4 Mitochondrial dysfunction is characterized by decreased expression of mitochondrial components and transcription factors involved in mitochondrial biogenesis, as well as defects in the assembly of respiratory complexes.3,5–7 Abnormal mitochondrial respiration can result in oxidative stress,8 uncoupling of the oxidative pathways from mitochondrial ATP synthesis,9 and subsequent failure of cellular energetic processes.2,10,11 Recent discoveries show that inefficient metabolism because of mitochondrial dysfunction in skeletal muscle and vascular smooth muscle can cause the elevation of systolic blood pressure and may be involved in the development of cardiovascular conditions, such as hypertension.3,4,12
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, including essential hypertension.13–15 The current work investigates the molecular basis of mitochondrial dysfunction in the brain in hypertension. We have applied various complementary techniques, such as a novel complex assembly analysis method based on mass spectrometric abundance indexes and other standard methods, including differential 2D-gel electrophoresis aided by mass spectrometry, immunoblotting, and enzymatic assays. Our findings provide strong and novel evidence of previously unknown assembly and enzymatic activity defects in brain mitochondrial respiratory complexes in hypertension. These defects are present in the brain stem and can, therefore, impair the systemic control of blood pressure.
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Methods |
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Please see the online supplement (available at http://hyper.ahajournals. org) for the expanded Methods section.
Systolic Blood Pressure Measurement
Systolic blood pressure in conscious male 12-week–old spontaneously hypertensive rats (SHRs) or age-matched Wistar Kyoto rats (normotension control) was measured using a computerized rat tail-cuff technique (Kent Scientific Corporation; n=4 in each group).
Proteomic Analysis
To fractionate and analyze the brain mitochondrial proteome and mitochondrial complexes, we used 2D-difference gel electrophoresis (DIGE)/mass spectrometry and 1D-SDS-PAGE/Western techniques combined with Blue-native–PAGE or sucrose gradient ultracentrifugation.16–18 Differentially expressed proteins were excised from preparative gels and digested with trypsin. Tryptic digests were analyzed using 2 separate instruments, an electrospray Q-ToF-2 (Micromass) mass spectrometer coupled with capillary high-performance liquid chromatography (Waters Corp) and a MALDI Ultraflex TOF-TOF (Bruker Daltonics). Protein identification from the tandem mass spectrometry (MS/MS) data was done by searching the National Center for Biotechnology Information nonredundant database (NCBInr_22.fasta, 3 651 628 sequences, 1 255 333 329 residues, and 35 247 sequences after taxonomy filter). The taxonomy parameter was open to entries from rodents. The determination of exponentially modified protein abundance index values19 was conducted using software (http://xome.hydra.mki.co.jp).
Mitochondrial Assays
Mitochondria complex I activity was measured spectrophotometrically at 340 nm, monitoring decrease of the reduced nicotinamide-adenine dinucleotide (NADH) concentration.20 The rate of mitochondrial oxygen consumption was measured using a polarographic system. Mitochondria production H2O2 was measured fluorometrically using the 2', 7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe. Mitochondrial ATP was determined by the luciferin/luciferase bioluminescence assay. In-gel ATPase activity was quantified by densitometric analysis of lead-phosphate precipitates generated during in-gel ATP hydrolysis as described.21
Statistical Analysis
Data analysis was conducted by either t test or 1-way ANOVA (Jandel SigmaStat 2.03 statistical software). Statistical significance was considered only when P
0.05 (ie, >95% confidence).
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Results |
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Rationale of Study Design
The general research strategy is illustrated in Figures S1 and S2.
Proteomic Analysis Reveals Metabolic and Mitochondrial Disorder in the Brain From Hypertensive Rats
The analysis of whole-brain mitochondria by the 2D-DIGE/MS/MS technique revealed 389 different protein spots across all of the gels (Figure S3). Thirty-four spots were consistently and significantly altered in hypertension versus normotension (Table); 27 nonredundant proteins were identified. Twenty of these 27 proteins are involved in cellular energetics including the following: (1) 7 respiratory complex subunits (Figure 1A); (2) 3 trichloroacetic acid cycle enzymes and 4 enzymes of the glycolytic pathway (Figure 1B); and (3) 6 proteins involved in other metabolic processes (Figure 1C).
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Hypertension-specific changes were not limited to cellular energetics. Also altered in hypertension were 4 chaperones (chaperonin GroEL, stress-70, 71-kDa heat shock cognate, and 78-kDa glucose-regulated protein) involved in processes such as the regulation of NO synthases,22 brain response to stress,23 and protein folding24 (Figure 1D).
The 27 altered proteins consisted of components from mitochondria (58%), cytoplasm (19%), cell surface (15%), and lysosome and cytoskeleton (4% each). Some of the altered proteins had >1 isoelectric point, and their abundance at these different isoelectric points was abnormal. This was the case for the respiratory complex subunits (ATP synthase subunits β and 
), enolase, glyceraldehyde 3-phosphate dehydrogenase, and the 78-kDa glucose-regulated protein.
Because the quantity of some respiratory complex subunits was decreased in hypertension (Figure 1A), we analyzed the integrity of these complexes. Blue-native–PAGE/Western analysis showed that marker subunits of complexes I, III, and IV had decreased abundance in hypertension (Figure 2A). These results were corroborated by normalizing the abundance of these complexes to prohibitin (Figure 2B), an inner-mitochondrial membrane marker, of which the expression did not change in hypertension (Figure 2C).
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Could the Respiratory Complexes Be Abnormally Assembled in Hypertension?
If the respiratory complexes were abnormally assembled in hypertension, then any missing subunits in the complexes could, in principle, be discovered by their abnormal behavior during complex isolation. Mitochondria preparations were analyzed by sucrose gradient ultracentrifugation/SDS-PAGE, proteins displaying abnormal fractionation were identified by MS/MS (Figure S2, S4A, and S4B), and their abundance (exponentially modified protein abundance index values)19 was estimated from mass spectral data (Table S2 and Figure S4C). In complex V, the F1-catalytic domain subunits β and , as well as the Fo-domain subunits β and , were downregulated in hypertension (Figure S5A through S5C). This decrease was characterized by the following: (1) the occurrence of subunits β and in a light sucrose fraction (F3), suggesting their detachment from the fully assembled complex V (clustered in fractions F4 through F7; Figure S5c); (2) the downregulation of subunits β and as first determined by 2D-DIGE (Figures 1A and S5D); and (3) the decrease in complex V activity as measured by the lead phosphate in-gel precipitation zymography assay (Figure S5E). In complex I, 2 of the 8 Fe-S cluster-containing proteins of the peripheral arm of complex I (Fe-S, 24 kDa, and Fe-S protein 8, 23 kDa) and β subcomplex 5 (a component of the hydrophobic protein in the membrane arm) decreased in abundance in hypertension (Figure S5F through S5H). To validate these observations, we targeted the 24-kDa Fe-S subunit. This nuclear encoded protein is situated in the input module that transfers electrons from NADH via flavin mononucleotide onto the chain of Fe-S clusters and is, therefore, critical for complex I activity.25 Using mass spectrometry, we failed to detect the 24-kDa subunit in fractions F4 through F7 in hypertension, whereas complex I was clustered in these fractions in normotension (Figure S5F and S5H). Interestingly, analysis by SDS-PAGE/Western showed that the total abundance of the Fe-S 24-kDa subunit was almost unchanged (data not shown). The findings suggested a loss of the 24-kDa Fe-S subunit from complex I in hypertension (Figure S5I). Accordingly, the NADH oxidoreductase activity of complex I in the presence of 2 different electron acceptors, decylubiquinone and potassium ferricyanide, was significantly decreased (Figure S5J).
Is the Mitochondrial Dysfunction in Hypertension Responsive to Pharmacological Drugs?
Based on our previous research,26,27 we examined the involvement of matrix metalloproteinases (MMPs) in the development of mitochondrial dysfunction. RT-PCR analysis detected MMP-7 in the brain stem, limbic system, and cerebral cortex (Figure S6), consistent with other reports.28 Treatment of SHR with doxycycline, a broad-spectrum MMP inhibitor (19.2 mg/d from week 7 to 12), did not generally affect protein quantity as determined by 2D-DIGE (data not shown) but did normalize the fractionation profile of many proteins (Figure S4B). Doxycycline prevented assembly defects of subunits and β (in complex V), as well as the 24 kDa and the protein 8 of the Fe-S centers (in complex I). Doxycycline partially restored the activity of complexes V and I (Figure S5E and S5J).
Could Mitochondrial Dysfunction Affect Cardiovascular Homeostasis in Hypertension?
To address this question we targeted the brain stem. We observed a loss of the 24-kDa Fe-S subunit (Figure 3A) and a significant reduction of NADH oxidoreductase activity of complex I from the brain stem in hypertension (Figure 3B).
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Coupled (state 4 and state 3) and uncoupled respiration rates were significantly affected in hypertension (Figure 3C, left). State 4 respiration rate (ie, a measure of respiration when no ADP is available for the ATP synthase) was increased, suggesting that the basal-coupled rate of respiration because of mitochondrial membrane leakage was enhanced in hypertension. State 3 respiration rate (ie, a measure of respiration when ADP is available) was decreased (Figure 3C, left). This suggested a deficient capacity of mitochondria to metabolize oxygen and the uncoupling of oxidative phosphorylation from ATP synthesis.
The respiration rate in the uncoupled state (ie, that in the absence of proton gradient induced by adding the uncoupling agent, carbonylcyanide m-chlorophenylhydrazone; Figure 3C, left) and the respiratory control ratio (defined as state 3:state 4) were also decreased in hypertension (Figure 3C, right), indicating that the relative efficiency of metabolic coupling of the electron chain complexes is impaired. The respiration rate in the uncoupled state was also decreased relative to state 4 (calculated as uncoupled state:state 4), confirming that the respiratory rate in the absence of a proton gradient was diminished and indicating the reduced maximum capacity of electron transfer chain in hypertension (Figure 3C, right). Mitochondria from the hypertensive brain stem exhibited elevated generation of reactive oxygen species (Figure 3D) and decreased ATP production (Figure 3E).
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Discussion |
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We have found that the brains of hypertensive rats exhibit cellular energetic defects and mitochondrial dysfunction. Proteins involved in central metabolic processes have decreased abundance. Brain respiratory complexes exhibit previously unknown assembly defects. The ensuing mitochondrial dysfunction affects the brain stem and could, thus, impact the systemic regulation of blood pressure and, thereby, the development and progression of hypertension.
The Dysfunction of Complexes I and V in Hypertension
The combined results of 3 complementary proteomic approaches yielded a bona fide glimpse at the structural integrity of brain mitochondrial respiratory complexes as they occur in hypertension (for supplementary discussion, please see the data supplement). Although global protein analysis by 2D-DIGE suggested that many cellular energetic systems may be affected in hypertension, we focused on mitochondrial complexes I and V, the first and final enzymes in the respiratory chain.29,30 Our study revealed assembly defects in both complexes in hypertension. In complex I, these defects involved the loss of Fe-S centers (such as the 24-, 30-, and 23-kDa [protein 8] subunits), which would be expected to disrupt electron transfer. Indeed, enzyme activity assays using 2 electron acceptors (decylubiquinone and ferricyanide) confirmed decreased levels of the NADH oxidoreductase activity of complex I in hypertension. Through the catalytic phosphorylation of ADP to form ATP, complex V (F1Fo-type ATPase) plays a key role in energy metabolism in the brain, and structural alterations of complex V can result in disease.30 Consistently, our data suggest that functionally key subunits, such as β and , are lost, and enzymatic activity of complex V is decreased in hypertension, providing molecular insight into the metabolic disorder that occurs in this condition.12
Significance of Assembly Defects for the Mitochondrial Respiratory Chain
The perturbation of a single complex can be enough to disrupt the integrity of neighboring complexes within the respiratory chain. For instance, the targeted deletion of complex IV subunit IV31 induces the misassembly of both complex IV and complex I, despite the normal expression of all of the complex I subunits.31 This seemed to be the case for the Fe-S 24-kDa subunit in complex I and also for core protein 1 in complex III, of which the abundance did not change, whereas their levels in their parent complexes dropped with hypertension.
Evidence Involving Matrix Metalloproteinases in the Development of Mitochondrial Dysfunction
We suggest that mitochondrial dysfunction is part of the cellular response to agonists (such as catecholamines and angiotensin II), which are elevated and play a causal role in the development of hypertension in the SHR. These agonists activate MMPs such as MMP-7.26,32 Assuming that doxycycline acts primarily by inhibiting MMPs, such as MMP-7, the treatment of SHR with doxycycline revealed 2 novel effects of systemic MMP inhibition: preventing the occurrence of complex assembly defects found in hypertensive rats and improving the activity of respiratory complexes I and V. However, we cannot exclude that doxycycline effects were partly attributable to inhibition of the expression of other enzymes, such as NO synthases. Importantly, the data suggest that mitochondrial dysfunction is responsive to pharmacological manipulation, even in genetic models of hypertension, such as the SHR.
Localization of Mitochondrial Dysfunction to the Brain Stem
Having identified assembly defects at the whole-brain scale, we targeted the brain stem. The brain stem is involved in control of sympathetic nerve activity, the set point of arterial pressure and baroreflex control; these 3 mechanisms are essential for homeostatic regulation of arterial pressure.33 Our studies revealed proteomic abnormalities in connection with impaired respiration, deficient ATP production, and elevated ROS generation. The dysfunction of mitochondria in the brain stem in hypertension is likely to affect the regulation of cardiovascular homeostasis.
Perspectives
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. Our findings suggest that, in already-hypertensive SHRs, 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. Interestingly, mitochondrial dysfunction in the central nervous system has been extensively investigated for several neurodegenerative diseases, including vascular dementia, Alzheimer’s, Huntington’s, and Parkinson’s disease.34–37 It is striking that the dysfunction that occurs in these diseases shares many molecular commonalities with that found in the current research in the context of hypertension. Future research should further explore the emerging link among hypertension, mitochondrial dysfunction, and neurodegeneration and the cause-effect relationships.
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Acknowledgments |
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Sources of Funding
This work was supported by research grants of the Natural Sciences and Engineering Council and Canadian Institutes of Health Research (to C.F.-P.), through a Natural Sciences and Engineering Council grant (to J.S.), and through Canada Foundation for Innovation grants to M.J.E. and C.F.-P. C.F.-P. is a new investigator of Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.
Disclosures
None.
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Footnotes |
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The first 2 authors contributed equally to this article.
Received October 3, 2007; first decision October 29, 2007; accepted December 5, 2007.
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