Angiotensin II-NADPH oxidase-derived superoxide mediates diabetes-attenuated cell excitability of aortic baroreceptor neurons.
Angiotensin II-NADPH oxidase-derived superoxide mediates diabetes-attenuated cell excitability of aortic baroreceptor neurons.
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血管紧张素 II-NADPH 氧化酶衍生的超氧化物介导糖尿病减弱的主动脉压力感受器神经元的细胞兴奋性。
DOI：
10.1152/ajpcell.00214.2011
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Zheng,Hong
中科院分区：
文献类型：
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作者：
Li,Yu-Long;Zheng,Hong
超极化激活的环核苷酸门控（HCN）通道的过度激活参与糖尿病抑制结状神经节主动脉压力感受器神经元的兴奋性。这种参与与糖尿病患者的高发病率和死亡率相关的自主神经功能障碍有关。本研究探讨了血管紧张素II I型受体（AT 1 R）拮抗剂（氯沙坦），NADPH氧化酶抑制剂（夹竹桃素），和超氧化物歧化酶模拟物（tempol）对糖尿病结状神经元增强HCN电流和衰减细胞兴奋性的影响。在假手术和链脲佐菌素诱导的1型糖尿病大鼠，用全细胞膜片钳技术记录主动脉压力感受器神经元的HCN电流和细胞兴奋性。糖尿病大鼠结状神经节中血管紧张素II水平高于假手术大鼠（101.6 ± 4.8 vs. 38.9 ± 4.2 pg/mg蛋白，P< 0.05）。单细胞RT-PCR、Western blot、免疫荧光染色和化学发光分析结果显示，与假手术组相比，糖尿病组大鼠结状核神经元AT 1 R mRNA和蛋白表达、NADPH氧化酶组分蛋白表达以及超氧化物产生均增加。糖尿病大鼠主动脉压力感受器神经元的HCN电流密度高于假手术组，细胞兴奋性低于假手术组。氯沙坦（1 μM）、夹竹桃素（100 μM）和tempol（1 mM）使糖尿病大鼠主动脉压力感受器神经元中增强的HCN电流密度正常化，并增加细胞兴奋性。这些发现表明，内源性血管紧张素II-NADPH氧化酶-超氧化物信号传导有助于糖尿病大鼠主动脉压力感受器神经元中HCN电流的增强和细胞兴奋的抑制。
Overactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is involved in diabetes-depressed excitability of aortic baroreceptor neurons in nodose ganglia. This involvement links to the autonomic dysfunction associated with high morbidity and mortality in diabetic patients. The present study examined the effects of an angiotensin II type I receptor (AT1R) antagonist (losartan), a NADPH oxidase inhibitor (apocynin), and a superoxide dismutase mimetic (tempol) on the enhanced HCN currents and attenuated cell excitability in diabetic nodose neurons. In sham and streptozotocin-induced type 1 diabetic rats, HCN currents and cell excitability of aortic baroreceptor neurons were recorded by the whole cell patch-clamp technique. The angiotensin II level in nodose ganglia from diabetic rats was higher than that from sham rats (101.6 ± 4.8 vs. 38.9 ± 4.2 pg/mg protein,P< 0.05). Single-cell RT-PCR, Western blot, immunofluorescence staining, and chemiluminescence data showed that mRNA and protein expression of AT1R, protein expression of NADPH oxidase components, and superoxide production in nodose neurons were increased in diabetic rats compared with those from sham rats. HCN current density was higher and cell excitability was lower in aortic baroreceptor neurons from diabetic rats than that from sham rats. Losartan (1 μM), apocynin (100 μM), and tempol (1 mM) normalized the enhanced HCN current density and increased the cell excitability in the aortic baroreceptor neurons of diabetic rats. These findings suggest that endogenous angiotensin II-NADPH oxidase-superoxide signaling contributes to the enhanced HCN currents and the depressed cell excitation in the aortic baroreceptor neurons of diabetic rats.