游离脂肪酸受体 G 蛋白偶联受体 40 介导脂肪乳剂诱导的心肌保护作用。
Free Fatty Acid Receptor G-protein-coupled Receptor 40 Mediates Lipid Emulsion-induced Cardioprotection.
机构信息
From the Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California.
出版信息
Anesthesiology. 2018 Jul;129(1):154-162. doi: 10.1097/ALN.0000000000002195.
BACKGROUND
We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein-coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein-coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
METHODS
Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein-coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg · min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV).
RESULTS
G-protein-coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product: 2,186 ± 1,783 [n = 7] vs. 11,607 ± 4,347 [n = 8]; left ventricular developed pressure: 22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = -443 ± 262 vs. -1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR: 302 ± 17 vs. 312 ± 38; ejection fraction: 69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%).
CONCLUSIONS
G-protein-coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
背景
我们之前已经表明，脂肪乳（脂质乳剂）可以保护心脏免受缺血/再灌注损伤和布比卡因引起的心脏毒性。然而，确切的潜在机制尚不完全清楚。在这里，我们假设游离脂肪酸受体-1 或 G 蛋白偶联受体 40 在心脏中表达，并且脂质乳剂的心脏保护作用是通过 G 蛋白偶联受体 40 在两种缺血/再灌注损伤和布比卡因引起的心脏毒性的动物模型中介导的。
方法
用单独的脂肪乳（1%）或 G 蛋白偶联受体 40 拮抗剂（GW1100，10 μM）对 Langendorff 灌注的雄性小鼠心脏进行缺血/再灌注。此外，在雄性大鼠中用布比卡因（10mg/kg，IV）进行心脏毒性实验，然后单独用脂肪乳（20%，5ml/kg 推注，0.5ml·kg·min 维持，IV）或用 GW1100 预处理（2.5mg/kg，IV）。
结果
G 蛋白偶联受体 40 在啮齿动物心脏中表达。GW1100 消除了脂肪乳对缺血/再灌注引起的心脏保护作用，因为心率血压乘积和左心室发展压低于单独使用脂肪乳（心率血压乘积：2186±1783[n=7] vs. 11607±4347[n=8]；左心室发展压：22.6±10.4 vs. 63.8±20；P<0.0001）。脂质乳剂+GW1100 还显示 LV dP/dtmax 和 LV dP/dtmin 降低（dP/dtmax=749±386 vs. 2098±792，P<0.001；dP/dtmin=-443±262 vs. -1447±546，P<0.001）。在布比卡因引起的心脏毒性大鼠模型中，GW1100 预处理对 30 分钟后的心率（HR）和射血分数没有显著影响（HR：302±17 vs. 312±38；射血分数：69±3% vs. 73±4%）。然而，GW1100 预处理预防了脂质挽救，10 分钟后没有恢复。在对照组中，脂肪乳剂改善了 HR（10 分钟时 215±16），并在 10 分钟时完全挽救了左心室功能（射血分数=67±8%，缩短分数=38±6%）。
结论
G 蛋白偶联受体 40 在啮齿动物心脏中表达，并参与脂肪乳剂介导的缺血/再灌注损伤和布比卡因引起的心脏毒性的心脏保护作用。
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