Nifedipine indirectly upregulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways
Nifedipine indirectly upregulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways
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DOI：
10.1161/01.cir.0000021924.02006.ba
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发表时间：
2002-07-16
期刊：
影响因子：
37.8
通讯作者：
Ogihara, T
中科院分区：
文献类型：
--
作者：
Fukuo, K;Yang, J;Ogihara, T
背景-钙拮抗剂可使许多心血管疾病的内皮功能障碍恢复正常。然而，目前还没有已知的内皮细胞(ECs)中钙拮抗剂的受体。我们假设血管平滑肌细胞(VSMCs)参与了钙拮抗剂使内皮功能障碍正常化的机制。方法与结果：通过与内皮细胞和VSMCs的共培养研究，确定VSMCs是否介导了钙拮抗剂硝苯地平诱导的内皮细胞超氧化物歧化酶(SOD)活性和表达的调节。硝苯地平可诱导大鼠主动脉段超氧化物歧化酶活性升高，但对单独培养的血管内皮细胞和血管平滑肌细胞的超氧化物歧化酶表达或活性无影响。然而，当内皮细胞与VSMCs共同培养时，硝苯地平上调了内皮细胞中SOD的表达和活性。硝苯地平可刺激VSMCs产生血管内皮生长因子(VEGF)，这种刺激作用可被缓激肽B-2受体拮抗剂HOE-140所阻断。抗血管内皮生长因子的中和抗体可抑制硝苯地平对内皮细胞超氧化物歧化酶的上调作用。此外，重组血管内皮生长因子可诱导内皮细胞超氧化物歧化酶表达水平升高，硝苯地平处理的血管平滑肌细胞培养上清液可促进内皮细胞产生NO。结论：钙拮抗剂硝苯地平通过刺激血管内皮细胞分泌血管内皮生长因子间接上调血管内皮细胞超氧化物歧化酶的表达。这一发现可能会进一步深入了解钙拮抗剂在心血管疾病中的有益作用的机制。
Background-Calcium antagonists normalize endothelial dysfunction in many cardiovascular diseases. There is no known receptor, however, for calcium antagonists in endothelial cells (ECs). We hypothesized that vascular smooth muscle cells (VSMCs) are involved in the mechanism underlying the normalization of endothelial dysfunction by calcium antagonists.Methods and Results-Coculture studies with ECs and VSMCs were performed to determine whether VSMCs mediate modulation of endothelial superoxide dismutase (SOD) activity and expression induced by the calcium antagonist nifedipine. Nifedipine induced upregulation of SOD activity in rat aortic segments but had no effect on SOD expression or activity in ECs or VSMCs cultured individually. When ECs were cocultured with VSMCs, however, nifedipine upregulated SOD expression and activity in ECs. Nifedipine stimulated vascular endothelial growth factor (VEGF) production from VSMCs, and this stimulation of VEGF production was abolished by HOE-140, an antagonist of the bradykinin B-2 receptor. A neutralizing antibody against VEGF inhibited the upregulation of endothelial SOD by nifedipine. In addition, recombinant VEGF induced an increase in the levels of SOD expression in ECs, and supernatant derived from nifedipine-treated VSMCs enhanced NO production from ECs. This increase in NO production by the supernatant was inhibited by preincubation of ECs with SOD antisense oligodeoxyribonucleotides.Conclusions-The calcium antagonist nifedipine indirectly upregulates endothelial SOD expression by stimulating VEGF production from adjacent VSMCs. This finding may provide further insight into the mechanism underlying the beneficial effects of calcium antagonists in cardiovascular diseases.