Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice

[Aims :] Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate...

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Published in:Journal of Atherosclerosis and Thrombosis 2021, Vol.28 (12), p.1349-1360
Main Authors: Kumiko Suto, Daiju Fukuda, Masakazu Shinohara, Byambasuren Ganbaatar, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Ken-ichi Hirata, Masataka Sata
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container_issue 12
container_start_page 1349
container_title Journal of Atherosclerosis and Thrombosis
container_volume 28
creator Kumiko Suto
Daiju Fukuda
Masakazu Shinohara
Byambasuren Ganbaatar
Shusuke Yagi
Kenya Kusunose
Hirotsugu Yamada
Takeshi Soeki
Ken-ichi Hirata
Masataka Sata
description [Aims :] Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. [Methods :] Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. [Results :] Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (P
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Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. [Methods :] Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. [Results :] Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (P<0.01), without affecting body weight. It also decreased circulating levels of AA (P<0.001), thromboxane B2 (P<0.001), prostaglandin E2, leukotriene B4 (P<0.05), and 5-hydroxyeicosatetraenoic acid (P<0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ12,14-prostaglandin J2, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P<0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P<0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function. [Conclusion :] Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.]]></description><identifier>ISSN: 1340-3478</identifier><language>jpn</language><publisher>Japan Atherosclerosis Society</publisher><ispartof>Journal of Atherosclerosis and Thrombosis, 2021, Vol.28 (12), p.1349-1360</ispartof><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4010</link.rule.ids></links><search><creatorcontrib>Kumiko Suto</creatorcontrib><creatorcontrib>Daiju Fukuda</creatorcontrib><creatorcontrib>Masakazu Shinohara</creatorcontrib><creatorcontrib>Byambasuren Ganbaatar</creatorcontrib><creatorcontrib>Shusuke Yagi</creatorcontrib><creatorcontrib>Kenya Kusunose</creatorcontrib><creatorcontrib>Hirotsugu Yamada</creatorcontrib><creatorcontrib>Takeshi Soeki</creatorcontrib><creatorcontrib>Ken-ichi Hirata</creatorcontrib><creatorcontrib>Masataka Sata</creatorcontrib><creatorcontrib>Department of Cardiovascular Medicine</creatorcontrib><creatorcontrib>Division of Cardiovascular Medicine</creatorcontrib><creatorcontrib>The Integrated Center for Mass Spectrometry</creatorcontrib><creatorcontrib>Department of Community Medicine and Medical Science</creatorcontrib><creatorcontrib>Tokushima University Graduate School of Biomedical Sciences</creatorcontrib><creatorcontrib>Department of Cardio-Diabetes Medicine</creatorcontrib><creatorcontrib>Kobe University Graduate School of Medicine</creatorcontrib><creatorcontrib>Division of Epidemiology</creatorcontrib><creatorcontrib>Department of Community Medicine for Cardiology</creatorcontrib><title>Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice</title><title>Journal of Atherosclerosis and Thrombosis</title><description><![CDATA[[Aims :] Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. [Methods :] Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. [Results :] Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (P<0.01), without affecting body weight. It also decreased circulating levels of AA (P<0.001), thromboxane B2 (P<0.001), prostaglandin E2, leukotriene B4 (P<0.05), and 5-hydroxyeicosatetraenoic acid (P<0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ12,14-prostaglandin J2, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P<0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P<0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function. [Conclusion :] Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.]]></description><issn>1340-3478</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqtUEtOwzAQzQIkyucOc4BGcuy2aZcRDbCgKAL2kWtPxFS2B8VJ1R6rF-FMOBJHYDG_997Mk-YqmxVqIXK1KNc32W2MByGUWi7lLLs06HVH-14POIcK3viIDj7QoRnoiNBgzyeK7FPbs6MOk5L7vJrotGPhHQ1-Jwh-LrBjO7qJnyfYjgYjNE5Hr6Emw1EHJguvmCwi6GCh8uiIJ-8IdbA8fKVZO9ieYzeGZMEBKMCW9B4HMrAjg_fZdaddxIe_epc9P9Wfjy-5R0tGOw6OArYHHvuQ-BZPpWV_1q0UsmiFkOtCtiJFeskmpZVQG1mUK6n-79IvsVd3-w</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Kumiko Suto</creator><creator>Daiju Fukuda</creator><creator>Masakazu Shinohara</creator><creator>Byambasuren Ganbaatar</creator><creator>Shusuke Yagi</creator><creator>Kenya Kusunose</creator><creator>Hirotsugu Yamada</creator><creator>Takeshi Soeki</creator><creator>Ken-ichi Hirata</creator><creator>Masataka Sata</creator><general>Japan Atherosclerosis Society</general><scope/></search><sort><creationdate>2021</creationdate><title>Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice</title><author>Kumiko Suto ; Daiju Fukuda ; Masakazu Shinohara ; Byambasuren Ganbaatar ; Shusuke Yagi ; Kenya Kusunose ; Hirotsugu Yamada ; Takeshi Soeki ; Ken-ichi Hirata ; Masataka Sata</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-medicalonline_journals_ex7domya_2021_002812_012_1349_136039217623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>jpn</language><creationdate>2021</creationdate><toplevel>online_resources</toplevel><creatorcontrib>Kumiko Suto</creatorcontrib><creatorcontrib>Daiju Fukuda</creatorcontrib><creatorcontrib>Masakazu Shinohara</creatorcontrib><creatorcontrib>Byambasuren Ganbaatar</creatorcontrib><creatorcontrib>Shusuke Yagi</creatorcontrib><creatorcontrib>Kenya Kusunose</creatorcontrib><creatorcontrib>Hirotsugu Yamada</creatorcontrib><creatorcontrib>Takeshi Soeki</creatorcontrib><creatorcontrib>Ken-ichi Hirata</creatorcontrib><creatorcontrib>Masataka Sata</creatorcontrib><creatorcontrib>Department of Cardiovascular Medicine</creatorcontrib><creatorcontrib>Division of Cardiovascular Medicine</creatorcontrib><creatorcontrib>The Integrated Center for Mass Spectrometry</creatorcontrib><creatorcontrib>Department of Community Medicine and Medical Science</creatorcontrib><creatorcontrib>Tokushima University Graduate School of Biomedical Sciences</creatorcontrib><creatorcontrib>Department of Cardio-Diabetes Medicine</creatorcontrib><creatorcontrib>Kobe University Graduate School of Medicine</creatorcontrib><creatorcontrib>Division of Epidemiology</creatorcontrib><creatorcontrib>Department of Community Medicine for Cardiology</creatorcontrib><jtitle>Journal of Atherosclerosis and Thrombosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumiko Suto</au><au>Daiju Fukuda</au><au>Masakazu Shinohara</au><au>Byambasuren Ganbaatar</au><au>Shusuke Yagi</au><au>Kenya Kusunose</au><au>Hirotsugu Yamada</au><au>Takeshi Soeki</au><au>Ken-ichi Hirata</au><au>Masataka Sata</au><aucorp>Department of Cardiovascular Medicine</aucorp><aucorp>Division of Cardiovascular Medicine</aucorp><aucorp>The Integrated Center for Mass Spectrometry</aucorp><aucorp>Department of Community Medicine and Medical Science</aucorp><aucorp>Tokushima University Graduate School of Biomedical Sciences</aucorp><aucorp>Department of Cardio-Diabetes Medicine</aucorp><aucorp>Kobe University Graduate School of Medicine</aucorp><aucorp>Division of Epidemiology</aucorp><aucorp>Department of Community Medicine for Cardiology</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice</atitle><jtitle>Journal of Atherosclerosis and Thrombosis</jtitle><date>2021</date><risdate>2021</risdate><volume>28</volume><issue>12</issue><spage>1349</spage><epage>1360</epage><pages>1349-1360</pages><issn>1340-3478</issn><abstract><![CDATA[[Aims :] Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. [Methods :] Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. [Results :] Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (P<0.01), without affecting body weight. It also decreased circulating levels of AA (P<0.001), thromboxane B2 (P<0.001), prostaglandin E2, leukotriene B4 (P<0.05), and 5-hydroxyeicosatetraenoic acid (P<0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ12,14-prostaglandin J2, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P<0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P<0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function. [Conclusion :] Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.]]></abstract><pub>Japan Atherosclerosis Society</pub></addata></record>
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title Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice
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