Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation
Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation
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DOI：
10.1159/000492577
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发表时间：
2018-01-01
期刊：
影响因子：
3.1
通讯作者：
Ishizawa, Keisuke
中科院分区：
文献类型：
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作者：
Imanishi, Masaki;Izawa-Ishizawa, Yuki;Ishizawa, Keisuke
背景/目标：硝苯地平（nitrosonifedipine，NO-NIF）是硝苯地平的光降解产物，具有较强的抗氧化和内皮保护作用，并能抑制多种心血管疾病。本研究的目的是研究NO-NIF对主动脉瘤形成的影响。方法：采用血管紧张素Ⅱ和β-氨基丙腈灌胃诱导小鼠主动脉瘤形成。二氢乙锭染色和硝基酪氨酸染色检测氧化应激。实时荧光定量PCR和免疫组化染色检测炎症相关基因的表达。为阐明NO-NIF抑制血管细胞粘附分子（VCAM）-1的作用机制，本研究采用体外培养的内皮细胞为实验材料。结果：NO-NIF可抑制腹主动脉瘤形成和主动脉扩张，而血压无明显变化。NO-NIF抑制弹性蛋白降解和基质金属蛋白酶-2mRNA表达。NO-NIF抑制活性氧-亲环素A的正反馈环。NO-NIF联合治疗可抑制炎症相关基因和内皮细胞VCAM-1 mRNA表达的上调。结论：NO-NIF有可能成为一种新的硝苯地平衍生的治疗药物，通过直接改善主动脉结构来抑制主动脉瘤的形成，其具有很强的降低氧化应激和炎症的能力。
Background/Aims: We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation. Methods: The mice were infused with -aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. Results: NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae. Conclusion: NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.