D-4F在七氟烷处理对急性高糖血症小鼠血管保护中的作用及机制

中国临床药理学与治疗学 ›› 2017, Vol. 22 ›› Issue (7): 743-748.

D-4F在七氟烷处理对急性高糖血症小鼠血管保护中的作用及机制

刘若海¹，卢园园¹，李丽伶²，沈露露¹，曹红³，李军¹，李旭³

¹温州医科大学附属第二医院麻醉科，温州 325027，浙江；²温州医科大学附属第一医院麻醉科，温州 325000，浙江； ³温州医科大学仁济学院，温州 325035，浙江

收稿日期:2015-12-29 修回日期:2016-11-22 出版日期:2017-07-26 发布日期:2017-07-19
通讯作者: 李旭，女，博士，讲师，研究方向：心血管疾病。 E-mail：lixu0577@126.com
作者简介:刘若海，男，硕士，主治医生，研究方向：临床麻醉。 E-mail：liuruuohai@163.com
基金资助:
浙江省自然科学基金青年项目（LQ17H020004）；浙江省教育厅一般科研项目（Y201431185）；温州市公益性科技计划项目（Y20160368）

D-4F enhances sevoflurane-induced vascular protection during acute hyperglycemia

LIU Ruohai¹, LU Yuanyuan¹, LI Liling², SHEN Lulu¹，CAO Hong³, LI Jun¹, LI Xu³

¹Department of Anesthesiology，the Second Affiliated Hospital of Wenzhou Medical Universtiy，Wenzhou 325027, Zhejiang, China; ² Department of Anesthesiology，the First Affiliated Hospital of Wenzhou Medical Universtiy，Wenzhou 325000, Zhejiang, China；³Renji Hospital of Wenzhou Medical Universtiy, Wenzhou 325035, Zhejiang, China

Received:2015-12-29 Revised:2016-11-22 Online:2017-07-26 Published:2017-07-19

摘要/Abstract

摘要：

目的: 观察apoA-1拟似物D-4F对七氟烷麻醉急性高糖血症小鼠的血管保护效应。方法: 实验一，雄性 C57BL/6J小鼠随机分4组（n=8）：对照组（CON组）、 D-4F组、急性高血糖组（AHG组）、 AHG+D-4F组，各组再进行吸入1.71%七氟烷(SEV)，检测各组血糖、主动脉血管环舒张功能、NO水平，Western blot检测内皮型一氧化氮合酶（eNOS）、磷酸化的eNOS（p-eNOS）、小凹蛋白（Cav-1）水平；实验二，人脐静脉血管内皮细胞（HUVEC）分别用5.5、20.0 mmol/L 的葡萄糖培养24 h，4 μg/mL 布雷德菌素A (BFA)和0.5 μg/mL D-4F孵育1 h，再进行SEV处理，检测ROS水平。结果: AHG组显示急性高血糖时血管的舒张能力下降，主动脉产生NO减少，Cav-1蛋白表达明显增强，eNOS活性下降。D-4F组显示加入D-4F并不能提高急性高血糖时的血管舒张能力，AHG+D-4F组显示给予SEV刺激后D-4F对血管的舒张有改善作用（P<0.01)，Cav-1蛋白表达下降，eNOS活性增强，NO生成增多。细胞实验显示SEV刺激下，HG+D-4F组ROS的生成下降，D-4F该功能并可被BFA所阻断。结论: D-4F可恢复SEV对急性高糖血症的血管保护功能，其机制可能与D-4F降低细胞内脂质筏区域Cav-1的耦合能力，增强脂质筏里eNOS的磷酸化，NO生成增多，ROS生成减少，减轻急性高血糖的血管损害有关。

关键词: 七氟烷, 心血管保护, D-4F, 急性高糖血症, 一氧化氮, 活性氧

Abstract:

AIM: To investigate the effects of sevoflurane-induced vascular protection by apolipoprotein A-1 mimetic D-4F during acute hyperglycemia. METHODS:Thrty-two male C57BL/6J mice were randomly assigned to 4 groups (n=8). Control group(CON group), D-4Fgroup, acute hyperglycemia group(AHG group), dextrose 2 g/kg (intraperitoneal injection); AHG+D-4F group. Blood glucose, isometric aortic tension, nitric oxide (NO) were measured in mice in the absence or presence of sevoflurane（1.71%）. Expressions of eNOS，p-eNOS，Cav-1 in arterioles were determined by Western blot.Superoxide generation species (ROS) were assessed in human umbilical vein endothelial cells (HUVEC) cultured in 5.5 or 20.0 mmol/L glucose with isoflurane (0.5 mmol/L) in the presence or absence of brefeldin A (BFA, 4 μg/mL) or D-4F (0.5 μg/mL). RESULTS: Vasodilation, phosphorylations, NO production of eNOS were decreased while Cav-1 expression was increased during acute hyperglycemia. D-4F increased endothelium-dependent vasodilation (P<0.01) while decreased Cav-1 expression and ROS production in HG+D-4F group after sevoflurane-induction.CONCLUSION: Polipoprotein A-1 mimetic D-4F can enhance sevoflurane-induced vascular protection, decrease Cav-1 expression and ROS production while increase NO production during acute hyperglycemia.

Key words: sevoflurane, vascular protection, D-4F, acute hyperglycemia, NO, ROS

中图分类号:

R965.2

刘若海，卢园园，李丽伶，沈露露，曹红，李军，李旭. D-4F在七氟烷处理对急性高糖血症小鼠血管保护中的作用及机制[J]. 中国临床药理学与治疗学, 2017, 22(7): 743-748.

LIU Ruohai, LU Yuanyuan, LI Liling, SHEN Lulu, CAO Hong, LI Jun, LI Xu. D-4F enhances sevoflurane-induced vascular protection during acute hyperglycemia[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(7): 743-748.

参考文献

［1］Ishihara M, Inoue I, Kawagoe T, et al. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction［J］.Am Heart J, 2003, 146(4):674-678.
［2］Lohr N, Kersten JR. Man overboard! Rescuing myocardium with membrane rafts［J］. Anesthesiology, 2010, 112(5):1076-1078.
［3］Amour J, Brzezinska AK, Jager Z, et al. Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms［J］. Anesthesiology, 2010, 112(3):576-585.
［4］Tsutsumi YM, Kawaraguchi Y, Horikawa YT, et al. Role of caveolin-3 and glucose transporter-4 in isoflurane-induced delayed cardiac protection ［J］. Anesthesiology, 2010, 112(5):1136-1145.
［5］Ou J, Wang J, Xu H, et al. Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet［J］. Circ Res, 2005, 97(11):1190-1197.
［6］Baotic I, Ge ZD, Sedlic F, et al. Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia［J］. Am J Physiol Heart Circ Physiol, 2013,305(2):H219-227.
［7］丁云录，成光宇，朱光泽,等. 消渴脂平胶囊治疗2 型糖尿病高脂血症实验研究［J］. 长春中医药大学学报, 2016 , 32(4):692-694.
［8］Sviridov D, Fidge N, Beaumier-Gallon G, et al. Apolipoprotein A-I stimulates the transport of intracellular cholesterol to cell-surface cholesterol-rich domains (caveolae)［J］. Biochem J, 2001, 358(Pt 1):79-86.
［9］Cohen AW, Combs TP, Scherer PE, et al. Role of caveolin and caveolae in insulin signaling and diabetes［J］. Am J Physiol Endocrinol Metab, 2003, 285(6):E1151-1160.
［10］Patel HH, Tsutsumi YM, Head BP, et al. Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1［J］. FASEB J, 2007, 21(7):1565-1574.
［11］Li X, Xing W, Wang Y, et al. Upregulation of caveolin-1 contributes to aggravated high-salt diet-induced endothelial dysfunction and hypertension in type 1 diabetic rats［J］. Life Sci , 2014, 113(1-2):31-39.
［12］Cassuto J, Dou H, Czikora I, et al. Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients［J］. Diabetes, 2014, 63:1381-1393.
［13］Pojoga LH, Yao TM, Opsasnick LA,et al. Dissociation of hyperglycemia from altered vascular contraction and relaxation mechanisms in caveolin-1 null mice［J］. J Pharmacol Exp Ther, 2014, 348:260-270.
［14］Peterson SJ, Kim DH, Li M,et al. The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice［J］. J Lipid Res, 2009, 50(7):1293-1304.
［15］Wool GD, Reardon CA, Getz GS. Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties［J］. J Lipid Res, 2008, 49(6):1268-1283.
［16］Bloedon LT, Dunbar R, Duffy D, et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients［J］. J Lipid Res, 2008, 49(6):1344-1352.
［17］Van den Brom CE, Boly CA, Bulte CS, et al. Myocardial perfusion and function are distinctly altered by sevoflurane snesthesia in diet-induced prediabetic rats［J］. J Diabetes Res, 2016;2016:5205631. doi: 10.1155/2016/5205631. Epub 2015 Dec 28.
［18］Yassine HN, Jackson AM, Reaven PD, et al. The application of multiple reaction monitoring to assess apo A-I methionine oxidations in diabetesand cardiovascular disease［J］.Transl Proteom, 2014,1(4/5):18-24.
［19］Khandouzi N, Shidfar F, Rajab A, et al. The effects of ginger on fasting blood sugar, hemoglobin a1c,apolipoprotein B,apolipoprotein a-I and malondialdehyde in type 2 diabetic patients［J］.Iran J Pharm Res, 2015,14(1):131-140.
［20］Ou Z, Ou J, Ackerman AW,et al. L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells［J］. Circulation,2003,107(11):1520-1524.

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