Vascular Research Lab. FIIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040, Madrid, Spain.
Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV), Madrid, Spain.
Sci Rep. 2017 Apr 27;7:46679. doi: 10.1038/srep46679.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK/Tnfsf12) is a cytokine implicated in different steps associated with vascular remodeling. However, the role of TWEAK under hyperglycemic conditions is currently unknown. Using two different approaches, genetic deletion of Tnfsf12 and treatment with a TWEAK blocking mAb, we have analyzed the effect of TWEAK inhibition on atherosclerotic plaque progression and stability in streptozotocin-induced diabetic ApoE deficient mice. Genetic inactivation of Tnfsf12 reduced atherosclerosis extension and severity in diabetic ApoE deficient mice. Tnfsf12 deficient mice display a more stable plaque phenotype characterized by lower lipid and macrophage content within atherosclerotic plaques. A similar phenotype was observed in diabetic mice treated with anti-TWEAK mAb. The proatherosclerotic effects of TWEAK were mediated, at least in part, by STAT1 activation and expression of proinflammatory target genes (CCL5, CXCL10 and ICAM-1), both in plaques of ApoE mice and in cultured vascular smooth muscle cells (VSMCs) under hyperglycemic conditions. Loss-of-function experiments demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured VSMCs. Overall, TWEAK blockade delay plaque progression and alter plaque composition in diabetic atherosclerotic mice. Therapies aimed to inhibit TWEAK expression and/or function could protect from diabetic vascular complications.
肿瘤坏死因子样凋亡微弱诱导因子（TWEAK/Tnfsf12）是一种细胞因子，涉及与血管重塑相关的不同步骤。然而，高血糖条件下 TWEAK 的作用目前尚不清楚。我们使用两种不同的方法，即 Tnfsf12 的基因缺失和 TWEAK 阻断 mAb 的治疗，分析了 TWEAK 抑制对链脲佐菌素诱导的糖尿病 ApoE 缺陷小鼠动脉粥样硬化斑块进展和稳定性的影响。Tnfsf12 基因缺失减少了糖尿病 ApoE 缺陷小鼠的动脉粥样硬化扩展和严重程度。Tnfsf12 缺陷小鼠表现出更稳定的斑块表型，其斑块内的脂质和巨噬细胞含量较低。在接受抗 TWEAK mAb 治疗的糖尿病小鼠中也观察到类似的表型。TWEAK 的促动脉粥样硬化作用至少部分是通过 STAT1 激活和促炎靶基因（CCL5、CXCL10 和 ICAM-1）的表达介导的，这在 ApoE 小鼠的斑块中和高血糖条件下培养的血管平滑肌细胞（VSMCs）中均如此。功能丧失实验表明，TWEAK 通过其受体 Fn14 和 STAT1 在培养的 VSMCs 中激活诱导促炎基因 mRNA 表达。总之，TWEAK 阻断可延缓糖尿病动脉粥样硬化小鼠的斑块进展并改变斑块组成。旨在抑制 TWEAK 表达和/或功能的治疗方法可能有助于预防糖尿病血管并发症。
