Wu Tao-Cheng, Chang Wei-Hung, Lu Hsin-Ying, Shih Chun-Che
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Vascul Pharmacol. 2022 Jun;144:106973. doi: 10.1016/j.vph.2022.106973. Epub 2022 Feb 26.
Tolvaptan has been approved for the treatment of autosomal dominant polycystic kidney disease and heart failure. However, the role of tolvaptan in patients with abdominal aortic aneurysm (AAA) has not been examined. Human aortic smooth muscle cells (HASMCs) were used as the in vitro model. Via Ang II infusion, experimental AAAs were induced in Apo-E knockout mice. In vitro study showed that tolvaptan suppressed matrix metalloproteinase (MMP) expressions (MMP-2 and MMP-9) and apoptosis in Ang II-stimulated HASMCs. In the Apo-E knockout mice with Ang II-induced AAA, the animals exhibited AAA formation with elastic lamina degradation, dilatation of the suprarenal aorta, increased macrophage infiltration and higher expressions of MMPs. Treatment with a high dose of tolvaptan prevented experimental AAA formation while preserving the elastic lamina structure, reducing inflammatory macrophages, and inhibiting gelatinolytic activity, MMP expressions and apoptosis of SMCs in aorta tissue. Specifically, tolvaptan reduced the expression of receptor-interacting protein kinase 3 (RIP3) and decreased apoptosis of SMCs. Our data demonstrated that tolvaptan reduces experimental AAA formation and dissection by inhibiting destruction of the aortic structure integrity and reducing inflammatory macrophage infiltration, MMP-2 and MMP-9 expressions, and apoptosis of vascular SMCs, indicating tolvaptan may have therapeutic potential for AAA and dissection.
托伐普坦已被批准用于治疗常染色体显性多囊肾病和心力衰竭。然而，托伐普坦在腹主动脉瘤（AAA）患者中的作用尚未得到研究。人主动脉平滑肌细胞（HASMCs）被用作体外模型。通过输注血管紧张素II（Ang II），在载脂蛋白E基因敲除小鼠中诱导实验性腹主动脉瘤。体外研究表明，托伐普坦可抑制Ang II刺激的HASMCs中基质金属蛋白酶（MMP）（MMP-2和MMP-9）的表达以及细胞凋亡。在Ang II诱导的腹主动脉瘤的载脂蛋白E基因敲除小鼠中，动物出现了伴有弹性层降解的腹主动脉瘤形成、肾上腺上主动脉扩张、巨噬细胞浸润增加以及MMPs表达升高。高剂量托伐普坦治疗可预防实验性腹主动脉瘤形成，同时保留弹性层结构，减少炎性巨噬细胞，抑制主动脉组织中的明胶酶活性、MMP表达以及平滑肌细胞凋亡。具体而言，托伐普坦降低了受体相互作用蛋白激酶3（RIP3）的表达并减少了平滑肌细胞凋亡。我们的数据表明，托伐普坦通过抑制主动脉结构完整性破坏以及减少炎性巨噬细胞浸润、MMP-2和MMP-9表达以及血管平滑肌细胞凋亡来减少实验性腹主动脉瘤形成和夹层分离，这表明托伐普坦可能对腹主动脉瘤和夹层分离具有治疗潜力。
