Abstract:
The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes\' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).
摘要:
据报道,来氟米特治疗的类风湿性关节炎(RA)患者发生心血管事件的可能性较低。然而,尚未研究来氟米特的抗动脉粥样硬化和心血管保护作用以及代谢。在这项研究中,我们评估了来氟米特对动脉粥样硬化的潜在益处,并揭示了其潜在机制.ApoE-/-小鼠单独喂食西方饮食(WD)或补充来氟米特(20mg/kg,口服灌胃,每天一次)持续12周。主动脉的样本,心,肝脏,血清,并收集巨噬细胞。我们发现,来氟米特可显着减少WD喂养的ApoE-/-小鼠的正面主动脉和主动脉根部的病变大小。来氟米特还能明显改善血脂异常,肝脏脂质含量降低,改善体内葡萄糖和脂质代谢紊乱。RNA-Seq结果表明,来氟米特可有效调节脂质代谢途径相关基因的表达。重要的是,来氟米特显著提高了体内AMPKα和乙酰辅酶A羧化酶(ACC)的磷酸化水平。此外,来氟米特及其活性代谢产物特立氟米特通过激活AMPK信号和抑制二氢乳清酸脱氢酶(DHODH)信号通路,抑制游离脂肪酸(FFA)诱导的AML12细胞的脂质积累,改善棕榈酸(PA)诱导的HUVEC的内皮功能障碍。我们提供的证据表明,来氟米特和特立氟米特通过调节脂质代谢和内皮功能障碍来改善动脉粥样硬化。我们的发现表明,抗风湿小分子药物来氟米特和特立氟胺有望用于治疗动脉粥样硬化和相关心血管疾病(CVD)。