Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms

Naofumi Amioka; Toru Miyoshi; Tomoko Yonezawa; Megumi Kondo; Satoshi Akagi; Masashi Yoshida; Yukihiro Saito; Kazufumi Nakamura; Hiroshi Ito

doi:10.3389/fcvm.2022.904215

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms

Front Cardiovasc Med. 2022 Jun 30:9:904215. doi: 10.3389/fcvm.2022.904215. eCollection 2022.

Authors

Naofumi Amioka¹, Toru Miyoshi¹, Tomoko Yonezawa², Megumi Kondo¹, Satoshi Akagi¹, Masashi Yoshida¹, Yukihiro Saito¹, Kazufumi Nakamura¹, Hiroshi Ito¹

Affiliations

¹ Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
² Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Abstract

Background: 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.

Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE ^- ^/ ^- mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).

Results: 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.

Conclusion: 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.

Keywords: abdominal aortic aneurysm; angiotensin II; catalase; oxidative stress; pemafibrate.