Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Atherosclerosis. 2013 Feb;226(2):364-72. doi: 10.1016/j.atherosclerosis.2012.12.005. Epub 2012 Dec 25.
Inflammation is an important molecular basis of atherosclerosis. Recent studies have shown that dihydropyridine calcium channel blockers (CCBs) can exert potent anti-inflammatory effects in models of vascular dysfunction. The purpose of the present study was to evaluate anti-inflammatory effects and mechanisms of lercanidipine and labedipinedilol-A, new generation dihydropyridine CCBs, in rat vascular smooth muscle cells (VSMCs) exposed to lipopolysaccharide (LPS) and interferon-γ (IFN-γ).
MTT, Griess reagent, RT-PCR, ELISA, gelatin zymography, immunocytochemistry and Western blotting were employed. We found that lercanidipine and labedipinedilol-A attenuated production of NO, ROS and TNF-α from LPS/IFN-γ-stimulated VSMCs. In addition, they both diminished the LPS/IFN-γ-induced expression of iNOS protein and mRNA, with attenuation of HMGB1 cytosolic translocation and subsequent extracellular release. Furthermore, they down-regulated MMP-2/MMP-9 activities, whereas expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, was up-regulated. Finally, we found that lercanidipine and labedipinedilol-A inhibited the nuclear translocation of NF-κB and suppressed the phosphorylation of JNK, p38 MAPK and Akt.
Lercanidipine and labedipinedilol-A can exert their anti-inflammatory effects through suppression of NO, ROS and TNF-α through down-regulation of iNOS, MMP-2/MMP-9, and HMGB1, with inhibition of signaling transduction of MAPKs, Akt/IkB-α and NF-κB pathways. These findings implicate a valuable role of new generation dihydropyridine CCBs lercanidipine and labedipinedilol-A for the treatment of inflammatory vascular diseases.
炎症是动脉粥样硬化的重要分子基础。最近的研究表明，二氢吡啶钙通道阻滞剂（CCB）在血管功能障碍模型中具有强大的抗炎作用。本研究旨在评估新型二氢吡啶类钙通道阻滞剂乐卡地平及拉贝地平在脂多糖（LPS）和干扰素-γ（IFN-γ）刺激的大鼠血管平滑肌细胞（VSMCs）中的抗炎作用及其机制。
采用 MTT、Griess 试剂、RT-PCR、ELISA、明胶酶谱、免疫细胞化学和 Western blot 法。我们发现乐卡地平和拉贝地平可减轻 LPS/IFN-γ 刺激的 VSMCs 中 NO、ROS 和 TNF-α 的产生。此外，它们均能减弱 LPS/IFN-γ 诱导的 iNOS 蛋白和 mRNA 的表达，减少 HMGB1 胞浆易位和随后的细胞外释放。此外，它们还下调 MMP-2/MMP-9 活性，同时上调基质金属蛋白酶抑制剂-1（TIMP-1）的表达，后者是 MMP-9 的抑制剂。最后，我们发现乐卡地平和拉贝地平抑制 NF-κB 的核转位，并抑制 JNK、p38 MAPK 和 Akt 的磷酸化。
乐卡地平和拉贝地平通过下调 iNOS、MMP-2/MMP-9 和 HMGB1，抑制 MAPKs、Akt/IkB-α 和 NF-κB 信号通路，从而发挥抗炎作用，减少 NO、ROS 和 TNF-α 的产生。这些发现表明新型二氢吡啶类钙通道阻滞剂乐卡地平和拉贝地平在治疗炎症性血管疾病方面具有重要作用。
