C反应蛋白对“敲除”低密度脂蛋白受体基因鼠、糖尿病鼠和 eNOS鼠动脉扩张作用的研究

摘要/Abstract

摘要： 目的: C 反应蛋白(CRP) 能够舒张正常鼠动脉平滑肌现已被发现。为了确定 CRP 与病理状态下动脉关系, 研究 CRP 扩张动脉的作用机制, 故对“敲除”低密度脂蛋白受体基因鼠[LDLr(-/-) ], “敲除”一氧化氮合成酶基因 eNOS 鼠[eNOS(-/-)] 和糖尿病鼠[db/db(+/ ?) ] 的主动脉和颈动脉进行实验研究。方法: 将 CRP 加入“敲除”LDL 受体基因鼠,“敲除”一氧化氮合成酶基因 eNOS 鼠和糖尿病鼠的主动脉和颈动脉中, 测定动脉张力, 并以同类、同性别正常鼠动脉为对照。结果: CRP 能不同程度的舒张由苯肾上腺素、前列腺素 F_2α 造成的正常鼠、LDLr(-/-) 、eNOS(-/-) 、db/db(+/ ?) 和内皮损伤鼠的主动脉和颈动脉收缩。CRP 舒张正常鼠主动脉达(66 ±8) %、颈动脉达(32±4) %;CRP 舒张 LDLr(-/-) 主动脉达(90 ±2) %、颈动脉达(54 ±3) %;CRP 舒张eNOS(-/-) 主动脉达(74 ±2) %、颈动脉达 (38 ±4) %。CRP 舒张 db/db(+/ ?) 主动脉达(47 ±6) %,颈动脉达(52±8) %;CRP 舒张内皮损伤鼠主动脉达(58±4) %, 然而颈动脉仅(9 ±4) %。结论: 对比CRP 舒张正常、LDLr(-/-) 、eNOS(-/-) 、db/db(+/ ?)和内皮损伤鼠动脉结果显示 CRP 是一非常强的血管平滑肌扩张剂, 其作用强度与 NO 相似。CRP 舒张动脉作用时间也与NO 相似。CRP 舒张 LDLr(-/-)鼠主动脉、颈动脉比别的鼠动脉更好, 显示 CRP 对动脉粥样硬化动脉作用最强。损伤内皮的颈动脉不能被 CRP 介导扩张, 但损伤内皮的主动脉仍能被CRP 介导扩张, 提示 CRP 扩张动脉平滑肌是部份依赖及不依赖内皮而直接作用的结果, 即 CRP 扩张动脉平滑肌是经双作用机制达到的。

关键词: C 反应蛋白, 一氧化氮, 低密度脂蛋白受体, 一氧化氮合成酶, db/db(-/ ?), 颈动脉, 主动脉, 内皮细胞

Abstract: AIM: To determine whether CRP is rele-vant to pathological arterial smooth muscle and to investi-gate both aorta and carotid arteries response to CRP in LDLr(-/-), eNOS(-/-) and db/db(+/ ?) mice arteries.METHODS: CRP was added in these kinds of arterial rings in order to check arterial tension response. Tension was recorded in isolated rings of aorta and carotid arteries taken from low-density lipoprotein receptor gene knockout mice, endothelial nitric oxide synthase knockout mice (eNOS(-/-) mice), diabetes mellitus mice (db/db+/ ? mice) and the corresponding wild -type strain.RE-SULTS:CRP relaxed aorta and carotid artery by phenyle-phine or prostaglandin F2α(PGF 2α) in normal mice, LDLr(-/-), eNOS(-/-) and db/db(+/ ?) mice.CRP relaxed aorta to (90±2) %and carotid to (54±3) %in LDLr(-/-), aorta to (74 ±2) % and carotid to (38 ± 4) %in eNOS, aorta to (47±6) %and carotid to (52± 8) % in db/db(+/ ?), and aorta to (66 ±8) % and carotid (32 ±4) %in normal mice. CRP-induced vessel dilation was abolished in carotid impaired endothelium, but not in aorta. CRP relaxed aorta, and carotid in LDLr (-/-) mice better than others.CRP only relaxed (9 ± 4) %in carotid endothelium damaged and relaxed (58± 4) % in aorta endothelium damaged. CONCLUSION: CRP is a very strong vascular muscle relaxation similar to NO.Its effect time is similar to that in NO. It is similar to normal mice arteries in CRP relaxing aorta and carotid, and independent of and depend on endothelium to dilate artery smooth muscle.

Key words: CRP, carotid, aorta, LDLr, db/db (+/ ?), eNOS

中图分类号:

R966

陈晓亮. C反应蛋白对“敲除”低密度脂蛋白受体基因鼠、糖尿病鼠和 eNOS鼠动脉扩张作用的研究[J]. 中国临床药理学与治疗学, 2005, 10(4): 436-442.

CHEN Xiao-liang. Effects of C-reactive protein on artery relaxation in LDLr(-/-), db/db (+/ ?) and eNOS mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(4): 436-442.

参考文献

1 Heinrich J, Schulte H, Schonfeld R, Kohler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain[J]. Thromb Haemost, 1995; 73:374-9
2 Ross R.The pathogenesis of atherosclerosis:a perspective for the 1990s[J]. Nature, 1993;362:801-9
3 Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al.Atherosclerosis:basic mechanisms:oxida-tion, inflammation, and genetics[J]. Circulation, 1995;91: 2488-96
4 Nieto FJ, Adam E, Sorlie P, Farzadegan H, MelnickJL, Com-stock GW, et al.Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis[J]. Circulation, 1996;94:922-7
5 Gupta S, Leatham EW, Carrington D, MendallMA, Kaski JC, Camm AJ.Elevated Chlamydia pneumoniae antibodies, cardio-vascular events, and azithromycin in male survivors of myocar-dial infarction[J]. Circulation, 1997;96:404-7
6 Taubes G.Cardiovascular disease, does Inflammation Cut to the Heart of the Matter[J]. Science, 2002;296:242-5
7 PasceriV, Willerson JT, Yeh ET.Direct proinflammatory effect of C-reactive protein on human endothelial cells[J]. Circula-tion, 2000:102:2165-8
8 Williams TJ.Oedema and vasodilatation in inflammation:the relevance of prostaglandins[J]. Postgrad Med J, 1977;53:660-2
9 Raud J.Vasodilatation and inhibition of mediator release repre-sent two distinct mechanisms for prostaglandin modulation of a-cute mast cell -dependent inflammation[J]. Br J Pharmacol, 1990;99:449-54
10 Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J.Hypercholesterolemia inlow density lipoprotein re-ceptor knockout mice and its reversal by adenovirus-mediated gene delivery[J]. J Clin Invest, 1993;92:883-93
11 Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, et al.Elevated blood pressures in mice lacking endothelial nitric oxide synthase[J]. Proc Natl Acad Sci U S A, 1996;93:13176-81
12 Chataigneau T, Feletou M, Huang PL, Fishman MC, Duhault J, Vanhoutte PM.Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice [J]. British Iournal Pharmacol, 1999;126:219-26
13 Brown MS, Goldstein JL.A receptor-mediated pathway for cholesterol homeostasis[J]. Science, 1986;232:34-7
14 Ishibashi S, Goldstein J, BrownM, Herz J, BurnsD.Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice[J]. J Clin Invest, 1994;93: 1885-93
15 Leonid S, Saquib S, Hartzel V, Schaff, Kenton J, Zehr, et al.C-reactive protein relaxes human vessel in vitro[J]. Arte-rioscler Thromb Vasc Biol, 2002;22:1865-8
16 Brayden JE, Nelson MT.Regulation of arterial tone by activa-tion of calcium-dependent potassium channels[J]. Science, 1992:256:532-5
17 Nelson MT, Quayle JM.Physiological roles and properties of potassium channels in arterial smooth muscle[J]. Am J Physi-ol, 1995;268:C799-822
18 Marsden PA, Heng HHQ, Scherer SW, Stewart RJ, Hall AV, Shi XM, et al.Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene[J]. J Biol Chem, 1993;268:17478-88
19 Zhang JL, Patel JM, Li YD, Block ER.Reductase domain cysteines 1048 and 1114 are critical for catalytic activity of hu-man endothelial cell nitric oxide synthase as probed by site-di-rected mutagenesis[J]. Biochem Biophys Res Commun, 1996; 226:293-300
20 Mansour SL, Thomas KR, Capecchi MR.Disruption of the proto-oncogene int -2 in mouse embryo-derived stem cells:a general strategy for targeting mutations to non-selectable genes [J]. Nature, 1986;336:743-8
21 Axel G, Ulrich KM, Decking, DING Z, Jens H, Hans-Jǜrgen B, Stefanie G, et al.Coronary hemodynamics in endothelial no synthase knockout mice[J]. Circulation Research, 1998;82: 186-94
22 Ignarro LJ, Byrns RE, Buga GM, Wood KS.Endothelium-de-rived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of ni-tric oxide radical[J]. Circ Res, 1987;61:866-79
23 Palmer RMJ, Ferrige AG, Moncada S.Nitric oxide release ac-counts for the biological activity of endothelium-derived relaxing factor[J]. Nature, 1987;327:524-6
24 Palmer RMJ, Ashton DS, Moncada S.Vascular endothelial cells synthesize nitric oxide from L-arginine[J]. Nature, 1988; 333:664-6
25 Lü scher TF, Noll G.The endothelium in coronary vascular nor-mal[A]. In:Braunwald E, ed.Heart Disease:A Textbook of CardiovascularMedicine.3rd ed[M]. Philadelphia, Pa:WB Saunders;1995:1-10
26 Harrison DG.Cellular and molecular mechanismsof endothelial cell dysfunction[J]. J Clin Invest, 1997;100:2153-7
27 Yaghoubi M, Oliver-Krasinski J, Cayatte AJ, Cohen RA.De-creased sensitivity to nitric oxide in the aorta of severely hyperc-holesterolemic apolipoprotein E-deficient mice[J]. J Cardiovasc Pharmacol, 2000;36:751-7
28 Ginsberg HN.Insulin resistance and cardiovascular disease[J]. J Clin Invest, 2000;106:453-8
29 Hayden, JM, Reaven PD.Cardiovascular disease in diabetes mellitus type 2:a potential role for novel cardiovascular risk factors[J]. Curr Opin Lipidol, 2000;11:519-28
30 Reaven GM.Pathophysiology of insulin resistance in human disease[J]. Physiol Rev, 1995;75:473-86

[1]	李若柠, 郭展立, 王媛, 孙建军. 血小板内皮聚集受体1及其介导的信号通路在血小板和内皮细胞中的作用研究进展[J]. 中国临床药理学与治疗学, 2023, 28(4): 438-444.
[2]	沈畅, 艾可龙, 胡长平. 低氧诱导因子1信号通路调控低氧性肺动脉高压研究进展[J]. 中国临床药理学与治疗学, 2023, 28(1): 114-120.
[3]	李苗, 俞沁玮, 江振洲, 张陆勇. LDLR的调控机制及其相关疾病与药物研究进展[J]. 中国临床药理学与治疗学, 2022, 27(8): 946-954.
[4]	林娜萍, 吴玉塘, 黄德奋, 许朝祥. miR-195-5p通过靶向调控FBXW7基因对氧化型低密度脂蛋白诱导的血管内皮细胞损伤的影响研究[J]. 中国临床药理学与治疗学, 2022, 27(2): 163-170.
[5]	杨永康, 李静, 饶廷彩, 张骏艳. 金丝桃苷通过调节自噬水平减轻心肌梗死小鼠心脏及胸主动脉的损伤[J]. 中国临床药理学与治疗学, 2021, 26(6): 601-608.
[6]	刘晓玲, 宋振蓉, 付媛, 陈敏, 师锐赞, 张轩萍. 熊果酸减轻高糖高脂诱导的人主动脉内皮细胞损伤[J]. 中国临床药理学与治疗学, 2021, 26(5): 522-531.
[7]	谢祥妹，黄志红，刘小菊，薛冰，蓝保珠. 叶酸片联合阿托伐他汀治疗对H型高血压患者同型半胱氨酸及颈动脉粥样硬化的影响[J]. 中国临床药理学与治疗学, 2020, 25(4): 455-459.
[8]	刘红丹，殷一红. 麒麟丸预防体外受精胚胎移植术后所致卵巢过度刺激综合征患者的疗效及对血浆相关指标的影响[J]. 中国临床药理学与治疗学, 2020, 25(2): 196-202.
[9]	周俊辉，孟宪慧. 序贯法测定羟考酮皮下注射用于Stanford A型主动脉夹层撕裂患者术前镇痛的半数有效剂量[J]. 中国临床药理学与治疗学, 2019, 24(8): 916-921.
[10]	全海燕，刘玉环，杨丽，阳芳，秦旭平. CGRP通过激活cAMP/PPARγ/eNOS途径改善血管内皮细胞胰岛素抵抗[J]. 中国临床药理学与治疗学, 2019, 24(6): 615-622.
[11]	严洁萍，章水均，张国兵，胡颖，罗丹，江红娟，李敏静. 丁苯酞对S-亚硝基化谷胱甘肽诱导脑微血管内皮细胞损伤的保护作用及机制研究[J]. 中国临床药理学与治疗学, 2019, 24(5): 517-522.
[12]	官俏兵，杨毅，郭丽，韩晨阳. 丁苯酞通过内质网应激途径抑制氧化低密度脂蛋白诱导血管内皮细胞凋亡的影响[J]. 中国临床药理学与治疗学, 2019, 24(4): 397-402.
[13]	于瀚，钟相根，李耘州，许宗颖，石少华，邓秀兰. 褪黑素对肝内胆汁淤积大鼠肝组织NO、MDA、GSH及NADPH的影响[J]. 中国临床药理学与治疗学, 2019, 24(11): 1221-1226.
[14]	高雪梅，张夏丽，陈敏，李洁，罗乐，韩斯嘉，董季，宋振蓉，张轩萍. 白杨素减轻人脐静脉内皮细胞的氧化应激损伤[J]. 中国临床药理学与治疗学, 2018, 23(9): 1022-1026.
[15]	刘静，王媚媚，刘录山，贺卫和，庹勤慧，文红艳. 烟酸姜黄素酯对低剪切应力诱导人脐静脉内皮细胞凋亡的影响及相关机制[J]. 中国临床药理学与治疗学, 2018, 23(8): 855-861.