NADPH氧化酶衍生的超氧阴离子介导心力衰竭兔中血管紧张素II增强的颈动脉体化学感受器敏感性。
NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits.
作者信息
Li Yu-Long, Gao Lie, Zucker Irving H, Schultz Harold D
机构信息
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
出版信息
Cardiovasc Res. 2007 Aug 1;75(3):546-54. doi: 10.1016/j.cardiores.2007.04.006. Epub 2007 Apr 19.
OBJECTIVE
A previous study from this laboratory showed that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin II type 1 (AT(1)) receptor in the carotid body (CB) are involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang II in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang II in CHF rabbits.
METHODS AND RESULTS
By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 muM (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (Delta-12.5+/-0.8 and Delta-12.8+/-0.9 imp/s at 40.7+/-2.3 mm Hg of PO(2), and Delta-5.6+/-0.5 and Delta-5.3+/-0.4 imp/s at 60.2+/-3.1 mm Hg of PO(2), p<0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (Delta-13.6+/-1.1 and Delta-13.7+/-0.9 imp/s at 40.9+/-3.1 mm Hg of PO(2), and Delta-6.7+/-1.2 and Delta-6.6+/-0.8 imp/s at 59.8+/-3.5 mm Hg of PO(2), p<0.05). In addition, mRNA and protein expressions of NADPH oxidase components (gp91(phox), p40(phox) and p47(phox)) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhanced superoxide anion production.
CONCLUSIONS
These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang II in CHF rabbits occurs via a NADPH oxidase-superoxide signaling pathway.
目的
本实验室之前的一项研究表明，内源性血管紧张素II（Ang II）水平升高以及颈动脉体（CB）中血管紧张素II 1型（AT(1)）受体上调参与了慢性心力衰竭（CHF）家兔外周化学感受器敏感性增强的过程。NADPH氧化酶衍生的超氧阴离子在许多器官中介导Ang II的作用。我们研究了该信号通路是否可能介导CHF家兔中由Ang II诱导的外周化学感受器敏感性增强。
方法与结果
通过记录离体标本中颈动脉窦神经的单单位活动，我们发现2 μM苯胂氧化物（PAO，NADPH氧化酶抑制剂）和1 mM TEMPOL（超氧化物歧化酶模拟物）不仅显著降低了Ang II增强的假手术家兔CB化学感受器对不同程度低氧的反应（在PO(2)为40.7±2.3 mmHg时，分别为Δ-12.5±0.8和Δ-12.8±0.9次/秒，在PO(2)为60.2±3.1 mmHg时，分别为Δ-5.6±0.5和Δ-5.3±0.4次/秒，p<0.05），还降低了CHF诱导的CB化学感受器对不同程度低氧反应的升高（在PO(2)为40.9±3.1 mmHg时，分别为Δ-13.6±1.1和Δ-13.7±0.9次/秒，在PO(2)为59.8±3.5 mmHg时，分别为Δ-6.7±1.2和Δ-6.6±0.8次/秒，p<0.05）。此外，与假手术家兔相比，CHF家兔CB中NADPH氧化酶成分（gp91(phox)、p40(phox)和p47(phox)）的mRNA和蛋白表达更高。此外，100 pM Ang II诱导假手术家兔CB匀浆中超氧化物生成增加，这与CHF家兔CB匀浆中的情况相似。PAO和Tempol抑制了Ang II和CHF增强的超氧阴离子生成。
结论
这些结果表明，CHF家兔中由Ang II介导的外周化学感受器敏感性增强是通过NADPH氧化酶-超氧阴离子信号通路发生的。
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