Department of orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215000, China; Dalian Jiuzhou Century Hospital, Dalian 116400, China.
Department of Orthopedics, The central Hospital of Enshi Autonomous Prefecture, Enshi 445000, China.
Int Immunopharmacol. 2019 Jan;66:347-353. doi: 10.1016/j.intimp.2018.11.035. Epub 2018 Dec 3.
Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of β-blockers or in whom treatment with β-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (I) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.
依伐布雷定最常用于治疗不能耐受β受体阻滞剂最大剂量或β受体阻滞剂治疗禁忌的心力衰竭恶化患者。虽然依伐布雷定被认为是一种高度选择性的“搞笑电流”（I）抑制剂，但这种药物作用的分子机制仍知之甚少。在本研究中，我们通过用肿瘤坏死因子-α（TNF-α）处理原代人软骨细胞，并测量关节软骨基质的降解以及各种酶和促炎细胞因子的表达，将依伐布雷定应用于骨关节炎。我们的结果表明，依伐布雷定显著阻断 TNF-α诱导的基质金属蛋白酶-3（MMP-3）、MMP-13、解整合素金属蛋白酶与血小板反应蛋白基序（ADAMTS）-4 和 ADAMTS-5 的基因和蛋白水平的上调。值得注意的是，依伐布雷定减弱了 TNF-α诱导的 II 型胶原和聚集蛋白聚糖在 mRNA 和蛋白质水平上的减少。此外，我们发现依伐布雷定抑制了白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）的表达和分泌以及活性氧物质（ROS）的产生。在机制上，我们的结果表明，依伐布雷定通过抑制核因子（NF-κB）p65 的核易位来消除 NF-κB 的激活。HCN2 的敲低增强了依伐布雷定对 TNF-α诱导的 II 型胶原和聚集蛋白聚糖降解的保护作用，表明依伐布雷定抑制 ECM 降解的作用可能是由 HCN2 介导的。我们的研究结果表明，依伐布雷定确实有可能应用于预防关节软骨基质的过度降解，从而防止骨关节炎的病理性发展和进展。
