Amioka Naofumi, Miyoshi Toru, Yonezawa Tomoko, Kondo Megumi, Akagi Satoshi, Yoshida Masashi, Saito Yukihiro, Nakamura Kazufumi, Ito Hiroshi
Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Front Cardiovasc Med. 2022 Jun 30;9:904215. doi: 10.3389/fcvm.2022.904215. eCollection 2022.
Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.
Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).
The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.
Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.
腹主动脉瘤（AAA）是一种危及生命的疾病，缺乏有效的预防治疗方法。本研究旨在评估选择性过氧化物酶体增殖物激活受体α（PPARα）激动剂匹伐他汀对AAA形成和破裂的影响。
通过皮下注射血管紧张素II（AngII）诱导小鼠实验性AAA 4周。口服给予匹伐他汀（0.1 mg/kg/天）。采用二氢乙锭染色评估活性氧（ROS）。
匹伐他汀治疗组和载体治疗组之间，AngII诱导的AAA大小无差异。然而，在匹伐他汀治疗的小鼠中观察到因AAA破裂导致的死亡率降低。匹伐他汀改善了AngII诱导的ROS，并降低了主动脉壁中白细胞介素-6和肿瘤坏死因子-α的mRNA表达。明胶酶谱分析表明匹伐他汀对基质金属蛋白酶-2活性有显著抑制作用。匹伐他汀预处理可抑制AngII诱导的人血管平滑肌细胞中ROS的产生，并伴有过氧化氢酶活性增加。小干扰RNA介导的过氧化氢酶或PPARα敲低显著减弱了匹伐他汀的抗氧化作用。
匹伐他汀在小鼠模型中预防了AAA破裂，同时减少了主动脉壁中的ROS、炎症和细胞外基质降解。对AAA破裂的保护作用部分由匹伐他汀在平滑肌细胞中诱导的过氧化氢酶的抗氧化作用介导。
