Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.
Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.
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Nitrosonifedipine 通过抗氧化作用改善血管紧张素 II 诱导的血管重塑。
DOI：
10.1007/s00210-012-0810-7
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发表时间：
2013
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et al
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作者：
Sakurada Takumi;et al
硝苯地平在光照下不稳定，分解为稳定的亚硝基类似物亚硝基硝苯地平（NO-NIF）。与硝苯地平相比，NO-NIF阻断钙通道的能力很弱。最近，我们已经证明，NO-NIF与不饱和脂肪酸反应，导致产生NO-NIF自由基，获得自由基清除活性。然而，NO-NIF对氧化应激相关的发病机制，如动脉粥样硬化和高血压的影响尚不清楚。在这项研究中，我们研究了NO-NIF对血管紧张素II（Ang II）诱导的血管重构的影响。NO-NIF可抑制Ang Ⅱ诱导的小鼠主动脉增厚和纤维化。NO-NIF降低了主动脉中的活性氧（ROS）和尿8-羟基-20-脱氧鸟苷。NO-NIF可抑制Ang II刺激的主动脉中p22 phox、CD 68、F4/80、单核细胞趋化蛋白-1和胶原I的mRNA表达。此外，NO-NIF抑制血管紧张素II诱导的细胞迁移和血管平滑肌细胞（VSMCs）的增殖。NO-NIF可使Ang Ⅱ诱导的VSMCs ROS水平降至对照组水平。NO-NIF抑制Ang Ⅱ诱导的Akt和表皮生长因子受体的磷酸化。NO-NIF对Ang Ⅱ诱导的VSMCs胞内Ca ~（2+）升高和蛋白激酶C-δ磷酸化无明显影响。电子顺磁共振谱显示NO-NIF自由基与培养的VSMCs反应不断产生。这些结果表明，NO-NIF改善血管紧张素II诱导的血管重塑通过衰减氧化应激。
Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22phox, CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca2+increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.