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(Circulation Research. 2009;105:886.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Transcriptional Upregulation of Mitochondrial Uncoupling Protein 2 Protects Against Oxidative Stress-Associated Neurogenic Hypertension

Samuel H.H. Chan, Chiung-Ai Wu, Kay L.H. Wu, Ying-Hao Ho, Alice Y.W. Chang, Julie Y.H. Chan

From the Center for Translational Research in Biomedical Sciences (S.H.H.C., A.Y.W.C.), Chang Gung Memorial Hospital-Kaohsiung Medical Center; Departments of Medical Education and Research (C.-A.W., K.L.H.W., J.Y.H.C.) and Neurology (Y.-H.H.), Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China.

Correspondence to Julie Y.H. Chan, PhD, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Taiwan 813, Republic of China. E-mail yhwa{at}isca.vghks.gov.tw

Rationale: 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.

Methods and Results: In Sprague–Dawley rats, transcriptional upregulation of UCP2 in RVLM by rosiglitazone, an activator of its transcription factor peroxisome proliferator-activated receptor (PPAR), 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 PPAR coactivator, PPAR coactivator (PGC)-1, and an increase in formation of PGC-1/PPAR 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.

Key Words: uncoupling proteins • mitochondrion • peroxisome proliferator-activated receptor • oxidative stress • blood pressure