Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
Department of Neurology, Medical University of Lublin, ul. Jaczewskiego 8, 20-090 Lublin, Poland.
Eur J Pharmacol. 2019 May 5;850:180-189. doi: 10.1016/j.ejphar.2019.02.014. Epub 2019 Feb 12.
Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.
炎症和氧化应激是动脉粥样硬化形成过程中两个关键的过程。血小板激活因子乙酰水解酶（PAF-AH）是一种与血浆脂蛋白相关的酶，可降解氧化修饰的脂蛋白中产生的促炎脂质。大量证据表明，基于肠促胰岛素的药物（一类新型抗糖尿病药物）可提供心血管保护作用，而这种作用不能归因于其降血糖作用。本研究旨在确定 GLP-1（胰高血糖素样肽-1）受体激动剂（艾塞那肽）和 DPP-4（二肽基肽酶-4）抑制剂（西他列汀）的抗动脉粥样硬化作用是否可能通过调节血小板激活因子乙酰水解酶（PAF-AH）活性/质量和抑制果糖喂养大鼠的低密度脂蛋白（LDL）氧化来实现。正常和果糖喂养大鼠（8 周）给予西他列汀（5 和 10mg/kg 口服）或艾塞那肽（5 和 10µg/kg，皮下注射）治疗（4 周）。用比色法测定血浆 PAF-AH 活性和磷脂酰胆碱（PC）浓度。用 ELISA 测定血浆 PAF-AH 浓度、氧化型 LDL（oxLDL）、己酰基-Lys 加合物（HEL）、溶血 PC、载脂蛋白 A-I（apoA-I）、载脂蛋白 B、血小板激活因子（PAF）、单核细胞趋化蛋白-1（MCP-1）和内皮素-1（ET-1）。艾塞那肽（5µg/kg，sc.）治疗果糖喂养大鼠 4 周可显著增加血浆 PAF-AH 活性（增加 33%，P<0.001），降低循环 oxLDL 水平（减少 42%，P<0.05）和 MCP-1 水平（减少 23%，P<0.01）。这些变化伴随着血浆 PC/溶血 PC（减少 47%，P<0.001）和 apoB/apoA-I 比值（减少 75%，P<0.001）的降低。艾塞那肽对酶活性的影响仅与代谢参数的轻微影响有关，且与体重减轻无关。艾塞那肽可抑制 LDL 的氧化修饰，而西他列汀则不能，这可能是由于其对血浆 PAF-AH 活性的有利影响。
