Transcriptional Upregulation of Mitochondrial Uncoupling Protein 2 Protects Against Oxidative Stress-Associated Neurogenic Hypertension
Transcriptional Upregulation of Mitochondrial Uncoupling Protein 2 Protects Against Oxidative Stress-Associated Neurogenic Hypertension
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DOI：
10.1161/circresaha.109.199018
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发表时间：
2009-10-23
影响因子：
20.1
通讯作者：
Chan, Julie Y. H.
中科院分区：
文献类型：
--
作者：
Chan, Samuel H. H.;Wu, Chiung-Ai;Chan, Julie Y. H.
基本原理：线粒体解偶联蛋白（mitochondrialuncoupling proteins，UCPs）是线粒体阴离子转运蛋白的超家族成员，它能使ATP合成与氧化磷酸化解偶联，并能减轻线粒体活性氧的产生。Objective：我们对UCP 2通过维持延髓头端腹外侧区（RVLM）活性氧稳态参与中枢心血管调节的假说进行了评估。我们还阐明了在RVLM.方法和结果：在Sprague-Dawley大鼠，转录上调UCP 2在RVLM的氧化应激反应的分子机制，罗格列酮，其转录因子过氧化物酶体增殖物激活受体（PPAR）γ的激活剂，降低线粒体过氧化氢水平在RVLM和全身动脉压。RVLM内微量注射血管紧张素II诱导的氧化应激增加了RVLM内UCP 2 mRNA或蛋白的表达，而NADPH氧化酶抑制剂、超氧化物歧化酶模拟物或p38丝裂原活化蛋白激酶抑制剂（SB 203580）可拮抗这种氧化应激，而细胞外信号调节激酶1/2抑制剂（U 0126）则不能拮抗这种氧化应激。血管紧张素II还以p38丝裂原活化蛋白激酶依赖性方式诱导PPAR γ共激活因子（PGC）-1 α的磷酸化，并增加PGC-1 α/PPAR γ复合物的形成。侧脑室注射血管紧张素II可促进RVLM和慢性升压反应中线粒体过氧化氢生成的增加，UCP 2基因敲除可增强这种作用，但罗格列酮可减弱这种作用。这些结果表明，线粒体UCP 2的转录上调响应于超氧化物的升高，在RVLM和神经源性神经损伤中活性氧产生的反馈调节中起着积极的作用。与慢性氧化应激相关的高血压。(Circ Res. 2009; 105：886-896）。
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)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 PPAR gamma coactivator, PPAR gamma coactivator (PGC)-1 alpha, and an increase in formation of PGC-1 alpha/PPAR gamma 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. (Circ Res. 2009; 105: 886-896.)