476-P: Pemafibrate, a PPAR Alpha Agonist, Attenuates Neointima Formation after Vascular Injury in Nondiabetic and Diabetic Mice

Abstract

Recently, the prevention of cardiovascular events has become one of most important purpose of diabetes care. We have previously reported that GLP-1 receptor agonist exendin-4 (BBRC 2011) and DPP-4 inhibitor linagliptin (Cardiovasc Diabetol 2014) attenuate neiontima formation after vascular injury. On the other hand, PPAR agonist is also reported its vascular protective effect. Then, we examined whether selective PPAR alpha agonist pemafibrate could attenuate neointima formation after vascular injury and vascular smooth muscle cell (VSMC) proliferation. We performed endothelial denudation injury in mice treated with high fat diet (HFD) or normal chow. Orally administered pemafibrate significantly attenuated neointima formation after vascular injury in both HFD and normal chow mice. Interestingly, pemafibrate increased serum FGF-21 concentration and decreased serum insulin concentration in HFD mice. In addition, body weight was slightly but significantly decreased by pemafibrate in HFD mice. In vitro experiments, pemafibrate attenuated VSMC proliferation in growth curve in a dose dependent manner, but not another PPAR alpha agonist bezafibrate. This suggested that the attenuation of VSMC proliferation by pemafibrate could be the drug effect, not class effect of PPAR alpha agonist. BrdU assay revealed that pemafibrate inhibited DNA synthesis in VSMC dose-dependently. In cell cycle distribution, G1 to S phase entry was significantly inhibited by pemafibrate in flow cytometry analysis. However, apoptosis was not induced by pemafibrate in VSMC in TUNEL assay. These data suggested that pemafibrate attenuates neiontima formation after vascular injury and VSMC proliferation inhibiting cell cycle progression. Disclosure T. Horikawa: None. T. Nomiyama: None. H. Takahashi: None. T. Kawanami: None. Y. Hamaguchi: None. T. Tanaka: None. T. Yanase: None.