A novel selective PPARα modulator, pemafibrate promotes ischemia-induced revascularization through the eNOS-dependent mechanisms

Kuroda, Hiroshi; Ohashi, Koji; Ogawa, Hayato; Otaka, Naoya; Takikawa, Tomonobu; Fang, Lanlan; Ozaki, Yuta; Takefuji, Mikito; Murohara, Toyoaki; Ouchi, Noriyuki

doi:10.1371/journal.pone.0235362

Cited by 13 publications

(11 citation statements)

References 43 publications

(50 reference statements)

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“…Therefore, further elucidation is required. In addition to our study, previous reports demonstrated a vascular protective effect of pemafibrate using other vascular cells, such as endothelial cells [25] and macrophages [26], suggesting that this effect of pemafibrate is not cell-type specific.…”

Section: Discussionsupporting

confidence: 77%

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

Horikawa

Kawanami

Hamaguchi

et al. 2020

Heliyon

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Recently, the prevention of cardiovascular events has become one of the most important aims of diabetes care. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported to have vascular protective effects. Here, we examined whether pemafibrate, a selective PPAR alpha agonist, attenuated neointima formation after vascular injury and vascular smooth muscle cell (VSMC) proliferation. We performed endothelial denudation injury in mice treated with a high-fat diet (HFD) or normal chow. Orally administered pemafibrate significantly attenuated neointima formation after vascular injury in HFD and normal chow mice. Interestingly, pemafibrate increased the serum fibroblast growth factor 21 concentration and decreased serum insulin concentrations in HFD mice. In addition, body weight was slightly but significantly decreased by pemafibrate in HFD mice. Pemafibrate, but not bezafibrate, attenuated VSMC proliferation in vitro. The knockdown of PPAR alpha abolished the anti-VSMC proliferation effect of pemafibrate. BrdU assay results revealed that pemafibrate dose-dependently inhibited DNA synthesis in VSMCs. Flow cytometry analysis demonstrated that G1-to-S phase cell cycle transition was significantly inhibited by pemafibrate. Pemafibrate attenuated serum-induced cyclin D1 expression in VSMCs. However, apoptosis was not induced by pemafibrate as assessed by the TUNEL assay. Similar to the in vitro data, VSMC proliferation was also decreased by pemafibrate in mice. These data suggest that pemafibrate attenuates neointima formation after vascular injury and VSMC proliferation by inhibiting cell cycle progression.

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Section: Discussionsupporting

confidence: 77%

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

Horikawa

Kawanami

Hamaguchi

et al. 2020

Heliyon

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“…The protective effects of PEM have been documented in extrahepatic organs both in mouse experiments and in the clinical setting. For example, PEM promoted ischemia-induced revascularization through eNOS-dependent mechanisms in mice [ 35 , 36 ]. PEM also attenuated neointima formation after vascular injury in mice fed normal chow and a high-fat diet [ 36 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

et al. 2022

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Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.

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“…Inhibitors of nitric oxide synthase reduced the development but not the magnitude of acute morphine antinociceptive tolerance (Wolińska et al, 2021; Xu et al, 1998). Under certain circumstances, such as ischemia, FGF21 activated endothelial nitric oxide synthase (Kawanishi et al, 2020). FGF21 effects on acute morphine tolerance may be occurring through some of these pathways.…”

Section: Discussionmentioning

confidence: 99%

Mice with High FGF21 Serum Levels Had a Reduced Preference for Morphine and an Attenuated Development of Acute Antinociceptive Tolerance and Physical Dependence

Dorval

Knapp

Majekodunmi

et al. 2021

Preprint

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As a result of the opioid epidemic, there is a desire to identify new targets for treating opioid use disorder. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55-degree C hot plate and the 55-degree C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had an attenuated preference for morphine, a reduced development of morphine-induced dependence, and a reduction in the development of acute morphine antinociceptive tolerance. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain treatment.

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A novel selective PPARα modulator, pemafibrate promotes ischemia-induced revascularization through the eNOS-dependent mechanisms

Cited by 13 publications

References 43 publications

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

Mice with High FGF21 Serum Levels Had a Reduced Preference for Morphine and an Attenuated Development of Acute Antinociceptive Tolerance and Physical Dependence

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