Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension.
BACKGROUND
Mitochondrial uncoupling proteins (UCPs) belong to a superfamily of mitochondrial anion transporters that uncouple ATP synthesis from oxidative phosphorylation and mitigates mitochondrial reactive oxygen species production.


OBJECTIVE
We assessed the hypothesis that UCP2 participates in central cardiovascular regulation by maintaining reactive oxygen species homeostasis in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons that maintain vasomotor tone located. We also elucidated the molecular mechanisms that underlie transcriptional upregulation of UCP2 in response to oxidative stress in RVLM.


RESULTS
In Sprague-Dawley rats, transcriptional upregulation of UCP2 in RVLM by rosiglitazone, an activator of its transcription factor peroxisome proliferator-activated receptor (PPAR)gamma, reduced mitochondrial hydrogen peroxide level in RVLM and systemic arterial pressure. Oxidative stress induced by microinjection of angiotensin II into RVLM augmented UCP2 mRNA or protein expression in RVLM, which was antagonized by comicroinjection of NADPH oxidase inhibitor (diphenyleneiodonium chloride), superoxide dismutase mimetic (tempol), or p38 mitogen-activated protein kinase inhibitor (SB203580) but not by extracellular signal-regulated kinase 1/2 inhibitor (U0126). Angiotensin II also induced phosphorylation of the PPARgamma coactivator, PPARgamma coactivator (PGC)-1alpha, and an increase in formation of PGC-1alpha/PPARgamma complexes in a p38 mitogen-activated protein kinase-dependent manner. Intracerebroventricular infusion of angiotensin II promoted an increase in mitochondrial hydrogen peroxide production in RVLM and chronic pressor response, which was potentiated by gene knockdown of UCP2 but blunted by rosiglitazone.


CONCLUSIONS
These results suggest that transcriptional upregulation of mitochondrial UCP2 in response to an elevation in superoxide plays an active role in feedback regulation of reactive oxygen species production in RVLM and neurogenic hypertension associated with chronic oxidative stress.
Chan
Samuel H H
SH
Center for Translational Research in Biomedical Sciences, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Republic of China.
Wu
Chiung-Ai
CA
Wu
Kay L H
KL
Ho
Ying-Hao
YH
Chang
Alice Y W
AY
Chan
Julie Y H
JY
D000255:Adenosine Triphosphate / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001808:Blood Vessels / Q000294:innervation*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D019069:Cell Respiration; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009861:Onium Compounds / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011725:Pyridines / Q000008:administration & dosage; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D045162:Thiazolidinediones / Q000008:administration & dosage; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014161:Transduction, Genetic; D000071246:Uncoupling Protein 2; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000255:Adenosine Triphosphate; D000804:Angiotensin II; D000975:Antioxidants; D002374:Catalase; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D007093:Imidazoles; D007473:Ion Channels; D024101:Mitochondrial Proteins; D019255:NADPH Oxidases; D009861:Onium Compounds; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011725:Pyridines; D016601:RNA-Binding Proteins; D000077154:Rosiglitazone; D013113:Spin Labels; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides; D045162:Thiazolidinediones; D014157:Transcription Factors; D000071246:Uncoupling Protein 2; D048051:p38 Mitogen-Activated Protein Kinases; D000099156:Superoxide Dismutase 2; C501429:Ppargc1a protein, rat; C000606290:SOD1 protein, human; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat; C007517:diphenyleneiodonium; C000606292:Sod1 protein, rat; C093642:SB 203580; C001803:tempol