延髓头端腹外侧区
血管紧张素II
下调和上调
氧化应激
NADPH氧化酶
内科学
化学
内分泌学
TFAM公司
活性氧
蛋白激酶A
线粒体
细胞生物学
线粒体生物发生
生物
激酶
受体
生物化学
医学
基因
血压
心率
作者
Samuel H.H. Chan,Chiung Ai Wu,Kou‐Juey Wu,Ying Hao Ho,Alice Y.W. Chang,Julie Y.H. Chan
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2009-10-23
卷期号:105 (9): 886-896
被引量:83
标识
DOI:10.1161/circresaha.109.199018
摘要
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)γ, 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 PPARγ coactivator, PPARγ coactivator (PGC)-1α, and an increase in formation of PGC-1α/PPARγ 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.
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