活性氧介导肾血管性高血压大鼠离体血管血管紧张素Ⅱ的缩血管效应的研究
|
摘要
高血压病是严重危害人类健康的常见病,主要特征为总外周阻力持续增高导致血压异常升高,并伴随着心脏和血管等结构性变化。其中,血管重构在高血压病的发生和病程发展中起关键性作用。目前,下肢动脉血管重构(vascular remodeling,VR)已成为国际上对高血压及其预后进行分析研究的热点,针对血管重构发生机制以逆转血管重构是防治高血压及其靶器官损害的重要靶标。高血压时血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)作为肾素—血管紧张素系统(rennin-angiotensin system,RAS)的主要递质,可诱导血管重构,内皮和平滑肌细胞血管紧张素Ⅰ型受体(angiotensin type 1 receptor,AT_1)表达增加,对缩血管物质的反应增强,这在高血压及其并发症的发生和维持中起关键性作用。活性氧(reactive oxygen species,ROS)作为细胞信号和调控的主要参与者,其生成与代谢的改变,参与了多种病理过程。我们近年研究发现中枢ROS介导了AngⅡ心交感传入反射增强、肾交感神经放电增加和血压增高效应。目前ROS和AngⅡ的关系成为人们关注的焦点。本研究以肾血管型高血压大鼠(renalhypertensive rats,RHR)股动脉为模型,选择国际上临床研究关注的下肢动脉为观察对象,探讨股动脉平滑肌中ROS是否调控血管基础张力,是否介导AngⅡ引起的缩血管效应以及介导AngⅡ缩血管效应的ROS是否主要来源于NAD(P)H氧化酶作用。确定ROS在高血压病血管重构中的功能性变化,为防治高血压病提供新思路和理论依据。
实验在RHR大鼠的离体去肉皮股动脉环上进行,以假手术(Sham)大鼠离体去内皮股动脉环作为对照,记录股动脉环平滑肌张力。以平滑肌张力变化值作为评价缩血管效应的指标。用硫代巴比妥酸法测定血管环平滑肌中丙二醛(MDA)水平,并用化学发光法测定血管环中超氧阴离子(O_2~-)水平,作为评价ROS水平的指标。主要研究结果如下:
1、AngⅡ引起RHR和Sham大鼠股动脉环平滑肌张力显著增加且具有明显的剂量效应关系;与Sham组相比,同等剂量的AngⅡ在RHR大鼠引起的缩血管效应更加明显。AT_1受体拮抗剂losartan引起RHR大鼠血管张力轻度降低,但对Sham大鼠无显著影响。losartan预处理可以完全阻断AngⅡ的缩血管效应。
2、超氧阴离子清除剂tempol和tiron轻度降低RHR大鼠股动脉环平滑肌张力,但对Sham大鼠无显著影响;SOD抑制剂DETC增强RHR和Sham大鼠股动脉环平滑肌张力,且在RHR大鼠引起的血管张力增加更加明显。Tempol和tiron预处理阻断RHR和Sham大鼠AngⅡ缩血管效应,而DETC预处理增强RHR组AngⅡ缩血管效应,但对Sham大鼠无显著影响。
3、NAD(P)H氧化酶抑制剂apocynin轻度降低RHR和Sham大鼠股动脉环平滑肌张力,其对RHR大鼠平滑肌张力的抑制作用更加明显。apocynin预处理完全阻断RHR和Sham大鼠AngⅡ引起的缩血管效应。
4、RHR大鼠股动脉环平滑肌中MDA和超氧阴离子水平显著升高,AngⅡ可使其水平进一步升高,且RHR大鼠升高效应更加明显;AT_1受体拮抗剂losartan对MDA和超氧阴离子水平无直接影响,但losartan预处理阻断RHR和Sham大鼠AngⅡ引起的平滑肌中MDA和超氧阴离子水平升高效应。
本研究表明高血压大鼠股动脉血管平滑肌中ROS调控血管张力,并介导AngⅡ兴奋AT_1受体引起的缩血管效应,NAD(P)H氧化酶是ROS生成的重要起源,血管平滑肌中AngⅡ与ROS异常在高血压大鼠股动脉平滑肌功能性血管重构中起重要作用。
Hypertension is one of the most common cardiovascular diseases. The incidence of the disease was as high as 18.8%and increased very quickly.However,the mechanism of hypertension is not completely known.The enhanced tension of vascular is a hallmark of hypertension and the degree of vascular remodeling(VR)is prognostic for survival in the hypertensive state.The tension of vascular,which is enhanced in the hypertensive state,contributes to an increase in VR in the hypertensive state.Previous studies suggested the abnormal action of AngⅡand AT_1 receptor in vascular smooth muscle(VSM)played an important part in vasoconstriction in hypertension.However,the mechanism responsible for the enhancement of the tension induced by AngⅡin VSM is not well understood.In the present study,we investigated the role of ROS in the regulatory effect of AngⅡon vasoconstriction and further elucidated the vascular mechanism responsible for modulation of the blood pressure.It will lay a foundation in finding new drugs for management of hypertension.
The study was carried out on isolated rings of femoral artery with endothelium removal in renal hypertensive rats(RHR)and those age-matched controls(Sham).Tension of VSM was recorded.Vascular reactivity to vasoactive substances was evaluated by the change of tension in rings of femoral artery.Superoxide anion level was measured with lucigenin-enhanced chemiluminescent method.Malondialdehyde (MDA)was determined by the thiobarbituric acid(TBA)spectrometric method,which indirectly indicated the ROS level in VSM.The primary findings were as follows.
1.Study on the role of ROS in modulating of the tension of VSM and mediating the effect of AngⅡon vasoconstriction.
Superoxide scavenger tempol or tiron showed a weak inhibitory effect on the enhanced tension in RHR and had no significant effect of the tension in Sham.Pretreatment with tempol or tiron significantly blocked the enhanced tension of VSM induced by AngⅡin both RHR and Sham. Superoxide dismutase(SOD)inhibitor diethyldithio-carbamic acid (DETC)augmented the tension of VSM in RHR,but did not significantly potentiate the effect of AngⅡon vasoconstriction in both RHR and Sham.
Incubation of AngⅡ,which elicited vasoconstriction,significantly increased MDA and superoxide anion levels in HR,and these effects were abolished by pretreatment with AT_1 receptor antagonist losartan in both RHR and Sham.
2.Study on the major source of the ROS in modulating the enhanced tension of VSM and mediating the vasoconstriction of AngⅡin RHR.
NAD(P)H oxidase inhibitor apocynin showed a weak inhibitory effect on the enhanced tension in RHR and had no significant effect of the tension in Sham.Pretreatment with apocynin significantly blocked the enhanced tension induced by AngⅡin both RHR and Sham.
In conclusion,the ROS in VSM are involved in the modulation of the enhanced tension of the VSM and contributed to the excitory effect of AngⅡon the vasoconstriction in RHR,the NAD(P)H oxidase is the major source of the ROS.
实验在RHR大鼠的离体去肉皮股动脉环上进行,以假手术(Sham)大鼠离体去内皮股动脉环作为对照,记录股动脉环平滑肌张力。以平滑肌张力变化值作为评价缩血管效应的指标。用硫代巴比妥酸法测定血管环平滑肌中丙二醛(MDA)水平,并用化学发光法测定血管环中超氧阴离子(O_2~-)水平,作为评价ROS水平的指标。主要研究结果如下:
1、AngⅡ引起RHR和Sham大鼠股动脉环平滑肌张力显著增加且具有明显的剂量效应关系;与Sham组相比,同等剂量的AngⅡ在RHR大鼠引起的缩血管效应更加明显。AT_1受体拮抗剂losartan引起RHR大鼠血管张力轻度降低,但对Sham大鼠无显著影响。losartan预处理可以完全阻断AngⅡ的缩血管效应。
2、超氧阴离子清除剂tempol和tiron轻度降低RHR大鼠股动脉环平滑肌张力,但对Sham大鼠无显著影响;SOD抑制剂DETC增强RHR和Sham大鼠股动脉环平滑肌张力,且在RHR大鼠引起的血管张力增加更加明显。Tempol和tiron预处理阻断RHR和Sham大鼠AngⅡ缩血管效应,而DETC预处理增强RHR组AngⅡ缩血管效应,但对Sham大鼠无显著影响。
3、NAD(P)H氧化酶抑制剂apocynin轻度降低RHR和Sham大鼠股动脉环平滑肌张力,其对RHR大鼠平滑肌张力的抑制作用更加明显。apocynin预处理完全阻断RHR和Sham大鼠AngⅡ引起的缩血管效应。
4、RHR大鼠股动脉环平滑肌中MDA和超氧阴离子水平显著升高,AngⅡ可使其水平进一步升高,且RHR大鼠升高效应更加明显;AT_1受体拮抗剂losartan对MDA和超氧阴离子水平无直接影响,但losartan预处理阻断RHR和Sham大鼠AngⅡ引起的平滑肌中MDA和超氧阴离子水平升高效应。
本研究表明高血压大鼠股动脉血管平滑肌中ROS调控血管张力,并介导AngⅡ兴奋AT_1受体引起的缩血管效应,NAD(P)H氧化酶是ROS生成的重要起源,血管平滑肌中AngⅡ与ROS异常在高血压大鼠股动脉平滑肌功能性血管重构中起重要作用。
Hypertension is one of the most common cardiovascular diseases. The incidence of the disease was as high as 18.8%and increased very quickly.However,the mechanism of hypertension is not completely known.The enhanced tension of vascular is a hallmark of hypertension and the degree of vascular remodeling(VR)is prognostic for survival in the hypertensive state.The tension of vascular,which is enhanced in the hypertensive state,contributes to an increase in VR in the hypertensive state.Previous studies suggested the abnormal action of AngⅡand AT_1 receptor in vascular smooth muscle(VSM)played an important part in vasoconstriction in hypertension.However,the mechanism responsible for the enhancement of the tension induced by AngⅡin VSM is not well understood.In the present study,we investigated the role of ROS in the regulatory effect of AngⅡon vasoconstriction and further elucidated the vascular mechanism responsible for modulation of the blood pressure.It will lay a foundation in finding new drugs for management of hypertension.
The study was carried out on isolated rings of femoral artery with endothelium removal in renal hypertensive rats(RHR)and those age-matched controls(Sham).Tension of VSM was recorded.Vascular reactivity to vasoactive substances was evaluated by the change of tension in rings of femoral artery.Superoxide anion level was measured with lucigenin-enhanced chemiluminescent method.Malondialdehyde (MDA)was determined by the thiobarbituric acid(TBA)spectrometric method,which indirectly indicated the ROS level in VSM.The primary findings were as follows.
1.Study on the role of ROS in modulating of the tension of VSM and mediating the effect of AngⅡon vasoconstriction.
Superoxide scavenger tempol or tiron showed a weak inhibitory effect on the enhanced tension in RHR and had no significant effect of the tension in Sham.Pretreatment with tempol or tiron significantly blocked the enhanced tension of VSM induced by AngⅡin both RHR and Sham. Superoxide dismutase(SOD)inhibitor diethyldithio-carbamic acid (DETC)augmented the tension of VSM in RHR,but did not significantly potentiate the effect of AngⅡon vasoconstriction in both RHR and Sham.
Incubation of AngⅡ,which elicited vasoconstriction,significantly increased MDA and superoxide anion levels in HR,and these effects were abolished by pretreatment with AT_1 receptor antagonist losartan in both RHR and Sham.
2.Study on the major source of the ROS in modulating the enhanced tension of VSM and mediating the vasoconstriction of AngⅡin RHR.
NAD(P)H oxidase inhibitor apocynin showed a weak inhibitory effect on the enhanced tension in RHR and had no significant effect of the tension in Sham.Pretreatment with apocynin significantly blocked the enhanced tension induced by AngⅡin both RHR and Sham.
In conclusion,the ROS in VSM are involved in the modulation of the enhanced tension of the VSM and contributed to the excitory effect of AngⅡon the vasoconstriction in RHR,the NAD(P)H oxidase is the major source of the ROS.
引文
1.Chobanian AV,Bakris GL,Black HR,Cushman WC,Green LA,Izzo JL,Jones DW,Materson BJ,Oparil S,Wright JT,Toccella EJ.Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure.Hypertension 2003;42:06-52.
2.中华人民共和国卫生部,中华人民共和国科学技术部,中华人民共和国国家统计局.中国居民营养与健康现状.中国心血管研究杂志 2004;2:19-22.
3.胡大一,贯彻循证医学的原则,做好我国心血管疾病的预防.心脏病学实践 2007 2007;1:8-18.
4.Gibbons GH,Dzau VJ.The emerging concept of vascular remodeling.N Engl J Med 1994;330:431-438.
5.Pandey N R,Benkirane K,Amiri F,et al.Effects of PPAR-γknock-down and hyperglycemia on insulin signaling in vascularsmooth muscle cells from hypertensive rats.Cardiovasc Phar-macol 2007;49:346-354.
6.Alan RO,Tara AM,Shufang QZ,et al.Hypertensive target organ damage is attenuated by a p38MAPK inhibitor:Role of systemic blood pressure and endothelial protection.Cardiovasc Res 2005;66:170-178.
7.Rizzoni D,Palombo C,Porteri E,et al.Relationships between coronary flowvasodilator capacity and small artery remodeling in hypertension patients.Hypertens 2003;21:625-631.
8. Cervenka L, Simova M, Maly J, Heller J. Role of the kidney in long-term regulation of blood pressure and the development of hypertension. Cesk Fysiol 2000; 49:116-133.
9. Hall JE, Brands MW, Henegar JR. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney.J Am Soc Nephrol 1999; 10: S258- S265.
10. Singh R, Singh AK, A lavi N, et al. Mechanism of increased angiotensin II levels in glomerular mesangial cells cultured in high glucose. J Am Soc Nephro 2003; 14: 873-880.
11. Fukai MA, Alexander RW, Akers M, et al. Angiotensin II receptor coupling to phospholipasse D is mediated by the βr subunits of heterotrimeric G_2protein in vascular smooth muscle cells. MolPharmacol 1999; 55: 142-149.
12. LI Weping, et al. Effects of atorvastatin on reactive oxygen species, expression of AT_1 receptor and p22(phox) in aorta of SHR, Clin Cardiol 2005;21: 104-108.
13. Zhong H, Alexander S, Christoph D, et al . Angiotensin II induced superoxide anion generation in human vascular endothelial cells : Role of membrane bound NADH/NADPH oxidases. Cardiovasc Res 1999; 44: 215-222.
14. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal disease. Circ Res 1998; 83:182-191.
15. Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptorgamma in vascular smooth muscle cells. Endocrinology 2001; 142: 3125-3134.
16. Diep QN, EI Mabrouk M, CohnJS, Endemann D, Amiri F, Virdis A, et al. Structure, endothelial function, cell growth, andinflammationin blood vessels of angiotension II -infused rats: role of peroxisome proliferators-activated receptor gamma. Circulation 2002; 105: 2296-2302.
17. Metcalfe BL, Huentelman MJ, Parilak LD, Taylor DG, Katovich MJ, Knot HJ, et al. Prevention of cardiac hypertrophy by angiotensin II type-2receptor gene transfer J. Hypertension 2004; 43: 1233-1238.
18. Garey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000; 35: 155-163.
19. Lassegue B, Griendling KK. Reactive oxygen species in hypertension: An update. Am J Hypertens 2004; 17: 852-860.
20. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004; 122: 339-352.
21. Owens GK, Schwartz SM. Vascular smooth muscle cell: hypertrophy and hyperploidy in the Goldblatt hypertensive rat. Circ Res 1983; 53: 491-501.
22. Snyder SH, Bredt DS. Biological role of nitric oxide. Sci Am 1992; 267: 28-35.
23. Rosendorff C. The rennin angiotensin system and vascular hypertrophy. Am Coll Cordial 1996; 28: 803-812.
24. Yu Y, Zhong MK, Li J, Sun XL, Xie GQ, Wang W, Zhu GQ. Endogenous hydrogen peroxide in paraventricular nucleus mediating cardiac sympathetic afferent reflex and regulating sympathetic activity. Pflug Arch-Eur J Physiol 2007; 454: 551-557.
25. Zhang Y, Yu Y, Zhang F et al. NAD(P)H oxidase in paraventricular nucleus contributes to the effect of angiotensin II on cardiac sympathetic afferent reflex. Brain Res 2006; 1082: 132-141.
26. Landmesser U, Cai H, Dikalov S, et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002; 40: 511-515.
27. Frenoux JM, Noirot B, Prost ED, et al. Very high alpha-tocopherol diet diminishes oxidative stress and hypercoagulation in hypertensive rats but not in normotensive rats. Med Sci M on it 2002, 8: BR401-BR407.
28. Park JB, Touyz RM, Chen X, et al. Chronic treatment with a super oxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke prone spontaneously hypertensive rats. Am J Hypertens 2002; 15: 78-84.
29. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 2001; 89: 408-414.
30. Park YM, Park MY, Suh YL, Park JB. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun 2004; 313: 812-817.
31. Abdi A,Johns EJ. Importance of the rennin angiotensin system in the generation of kidney failure in renovascular hypertension.Hypcrtens 1996;14:1131-1137.
32.戴勇,彭武建,徐卓佳.“两肾一夹”肾性高血压大鼠模型的改进.实验动物科学与管理 2006;2:35-41.
33.杜淑旭,张春雨,金红芳,杜军保,唐朝枢.二氧化硫衍生物舒张大鼠离体主动脉血管环的效应及其机制研究.北京大学学报(医学版)2006;6:25-31.
34.徐叔云,卞如濂,陈修主编.心血管系统药物实验法.药理实验方法学(第三版,人民卫生出版社)2003;8:941-1119.
35.Ohkawa H,Ohishi N,Yagi K.Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.Anal Biochem 1979;95:351-358.
36.Han Y,Shi Z,Zhang F,Yu Y,Zhong MK,Gao XY,Wang W,Zhu GQ.Reactive oxygen species in paraventricular nucleus mediates cardiac sympathetic afferent reflex in chronic heart failure rats.Eur J Heart Fail 2007;9:967-973.
37.Gao L,Wang W,Li YL,Schultz HD,Liu D,Cornish KG;et al.Superoxide mediates sympathoexcitation in heart failure:roles of angiotensin Ⅱ and NAD(P)H oxidase.Circ Res 2004;95:937-944.
38.Latini A,Scussiato K,Rosa RB,Leipnitz G,Llesuy S,Bello-Klein A,et al.Induction of oxidative stress by L-2-hydroxyglutaric acid in rat brain.Neurosci Res 2003;74:103-110.
39.Li JM,Shah AM.Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells.Biol Chem 2002;277:52-60.
40. Li Y, Zhu H, Kuppusamy P, Roubaud V, Zweier JL, Trush MA. Validation of lucigenin (bis-N-methylacridinium) as a chemilumigenic probe for detecting superoxide anion radical production by enzymatic and cellular systems. Biol Chem 1998; 273: 2015-2023.
41. Tai MH, Wang LL, Wu KL, Chan JY. Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Radic Biol Med 2005; 38: 450-462.
42. Dzau VJ, Gibbons GH, Morishita R, Pratt RE. New perspectives in hypertention research: potentials of vascular biology. Hypertention 1994; 23: 132-140.
43. Dzau VJ. Theodore cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047-1052.
44. Han Y, Runge MS, Brasier AR. Angiotensin II induces interleukin6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res 1999; 84: 695-703.
45. Reddan JR, Sevilla MD, Giblin FJ, et al. The superoxide dismutase mimic TEMPOL protects cultured rabbit lens epithelial cells from hydrogen peroxide insult. Exp Eye Res 1993; 56: 543-554.
46. Puri PL, Avantaggiati ML, Burgio VL, et al. Reactive oxygen intermediates (ROIs) are involved in the intracellular transduction of angiotensin II signal in C2C12 cells. Ann N Y Acad Sci 1995; 752: 394-405.
47. Sun C, Sellers KW, Sumners C, Raizada MK. NAD(P)H Oxidase Inhibition Attenuates Neuronal Chronotropic Actions of Angiotensin II. Circ Res 2005; 96: 659-666.
48. Akpaffiong MJ, Taylor AA. Antihypertensive and vesodiolator actions of antioxidants in SHR. Am J Hpertension 1998; 11: 1450-1460.
49. Koska J, Syrova D, Blazicek P, et al Malondialdehyele, lipofuscin and activity of antioxidant enzymes during physical exercise in patients with essential hypertension. Hypertensions 1999; 17: 529-535.
50. Greenstock CL, Miller RW. The oxidation of tiron by superoxide anion: Kinetics of the reaction in aqueous solution in chloroplasts. Biochim Biophys Acta 1975; 396: 11-16.
51. Yamada J, Yoshimura S, Yamakawa H, et al. Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation. Neurosci Res 2003; 45(1): 1-8.
52. Guzik TJ, Olszanecki R, Sadowski J et al. Superoxide dismutase activity and expression in human venous and arterial bypass graft vessels. Physiol Pharmacol 2005; 56: 313-323.
53. Pryor WA, Godber SS. Noninvasive measures of oxidative stress status in humans. Free Radic Biol Med 1991; 10: 177-184.
54. Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest 1982; 47: 412-426.
55. Müunzel T, Kurz S, Thoenes Rajagoplalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane bound NADH oxidase: A new action for an old drug. Clin Invest 1996; 98: 1465-1470.
56. Stolk J, Hiltermann TJ, Dijkman JH, Verhoeven AJ. Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Bio 1994; 11:95-102.
57. Ben Shaul V, Lomnitski L, Nyska A, et al. The effect of natural antioxidants NAO and apocynin on oxidative stress in the rat heart following LPS challenge. Toxicol Lett 2001; 123: 1-10.
58. Dodd O, Pearse DB. Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury. Am J Physiol Heart Circ Physiol 2000; 279: H303-H312.
59. Kazama K, Anrather J, Zhou P, et al. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 2004; 95: 1019-1026.
60. Souza HP, Cardounel AJ, Zweier JL. Mechanisms of free radical production in the vascular wall. Coron Artery Dis 2003; 14: 101-107.
61. Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003; 24: 471-478.
62. Zekry D, Epperson TK, Krause KH. A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia? IUBMB Life 2003; 55: 307-313.
63. Knapp LT, Klann E. Role of reactive oxygen species in hippocampal long-term potentiation: contributory or inhibitory? Neurosci Res 2002; 70: 1-7.
64. Suzukawa K, Miura K, Mitsushita J, et al. Nerve growth factor-induced neuronal differentiation requires generation of Racl-regulated reactive oxygen species. Biol Chem 2000; 275: 13175-13178.
65. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000; 86: 494-501.
66. Li JM, Shah AM. Mechanism of endothelial cell NADPH oxidase activation by angiotensin II: Role of the p47(phox) subunit. Biol Chem 2003; 278: 12094-12100.
67. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of agp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002; 105: 293-296.
68. Cifuentes ME, Rey FE, Carretero OA, Pagano PJ. Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin Il-infused mice. Am J Physiol Heart Circ Physiol 2000; 279: H2234-H2240.
69. Zimmerman MC, Dunlay RP, Lazartigues E, et al. Requirement for Racl-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain. Circ Res 2004; 95: 532-539.
70. Zhong H, Alexander S, Christoph D, et al. Angiotensin II induced superoxide anion generation in human vascular endothelial cells: Role of membrane bound NADH/NADPH oxidases. Cardiovasc Res 1999; 44: 215-222.
71. Karthikeyan VJ, Lip GY. Oxidative stress and hypertension. Int J Clin Pract 2006; 60: 1525-1527.
1.Chobanian AV,Bakris GL,Black HR,Cushman WC,Green LA,Izzo JL,Jones DW,Materson BJ,Oparil S,Wright JT,Toccella EJ.Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure.Hypertension 2003;42:1206-1252.
2.Gibbons GH,Dzau VJ.The emerging concept of vascular remodeling.N Engl J Med 1994;330:431-438.
3.Alan RO,Tara AM,Shufang QZ,et al.Hypertensive target organ damage is attenuated by a p38MAPK inhibitor:Role of systemic blood pressure and endothelial protection.Cardiovasc Res 2005;66:170-178.
4.王凡,刘国树.大动脉顺应性减退的机制研究.国外医学:心血管疾病分册 2005;32:275-278.
5.董现峰,洪华山.心血管病时冠状动脉微血管重构研究进展.中国动脉硬化杂志 2004;12:116-120.
6.Dzau VJ,Gibbons GH,Morishita R,Pratt RE.New perspectives in hypertention research:potentials of vascular biology.Hypertention 2004;23:132-140.
7.Fujii K,Umemoto S,Fujii A,et al.Angiotens in Ⅱ type 1receptorantagonis t downregulates nonmuscle myos in heavy chains in spontaneously hypertensive rat aorta.Hypertension 1999;33:975-980.
8.秦旭平,龙光,徐立朋,等.氯沙坦和培哚普利逆转高血压大鼠 心血管重构的比较.中国药理学通报 2004;20:1107-1111.
9.李留东,廖玉华,周子华,等.主动免疫AT_1受体对自发性高血压大鼠血管重构的影响.高血压杂志 2005;13:296-300.
10.Malek AM,Alper SL,Izumo S.Hemodynamic shear stress and its role in atherosclerosis.JAMA 1999;282:2035-2042.
11.Langille BL.Blood flow induced remodeling of the artery wall[A].In:Bevan JA,Kaley G,Rubanyi G,eds:Flow dependent regulation of vascular function.New York NY:Coxford 2005;2:277-299.
12.Barbee KA,Mundel T,Lal R,et al.Subcellular distribution of shear stress at the surface of flow2aligned and nonaligned endothelial monolayers.Am J Physiol 2002;268:H1765-H1772.
13.Kanai AJ,Strauss HC,Truskey GA,et al.Shear stress induces ATP in dependent transient cells,measureddirectly from vacular endothelialcells,measured directly with a porphyrinic microsensor.Circ Res 2003;77:284-293.
14.Fukai T,Siegfried MR,Ushio Fukai M,et al.Modulation of extracellular superoxide dismutase expression by angiotensin Ⅱ and hypertension.Circ Res 1999;85:23-28.
15.Somers MJ,Mavromatis K,Galis ZS,et al.Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt.Circulation 2000;101:1722-1728.
16.Han Y,RungeMS,BrasierAR.Angiotensin Ⅱ induces interleukin-6transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor kappa B transcription factors.Circ Res 1999;84:695-703.
17. Lingyun W, Jacques DC. Effect of superoxide on signaling pathways in smooth muscle cells from rats. Hypertension 1999; 34:247-253.
18. Rosendorff C. The rennin angiotensin system and vascular hypertrophy. J Am Coll Cordial 1996; 28: 803-812.
19. Berry C, Humilton CA, brosonan MJ, et al. Investigation into the sources of superoxide in human blood vessels Angioten II increase superoxide production in human internal mammary arteries. Circulation 2000; 101: 2206-2212.
20. Fukai MA, Alexander RW, Akers M, et al. Angiotensin II receptor coupling to phospholipasse D is mediated by the βr subunits of heterotrimeric G-protein in vascular smooth muscle cells. MoP harmacol 1999; 55: 142-149.
21. Touyz RM, Schiffrin EL. Ang II -stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension 1999; 34: 976-982.
22. Knauss TC, Jaffer FE, Abboud HE. Phosphatidic acid modulates DNA synthesis, phospholipase C and platelet derived growth factor mRNAs in cultured mesangial cells. Biol Chem 1990; 265: 14457-144631.
23. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186-195.
24. Arangino S, et al. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol 2003;83: 1417-1419.
25. Cagnacci A. Melatonin in relation to physiology in adult humans. Pineal Res 1999; 21: 200-213.
26. Skalak TC, Price RJ. The role of mechanical stress is in microvascular remodeling. Microcirculation 1996; 3: 143-165.
27. Gerber HP, McMurtrey A, Kowalski J, Yan MH, Keyt BA, Dixit V, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'2 kinase Akt signal transduction pathway: requirement for Flk21/ KDR activation. Biol Chem 1998; 273: 336-343.
28. Fukuo K, Hata S , Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, et al. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 2000; 27: 823-826.
29. Nicholson DW, Thornberry NA. Caspases killer proteases. Trends Biochem Sci 1997; 22: 299-306.
30. Pollman MJ, Naumovski L, Gibbons GH. Vascular cell apoptosis: Cell type specific modulation by transforming growth factor β1 in endothelial cells versus smooth muscle cells. Circulation 1999; 99: 019-026.
31. Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 449-456.
32. Sata M, Suhara T, Walsh K. Vascular endothelial cells and smooth muscle cells differ in their expression of Fas and Fas ligand and in their sensitivity to Fasligand-induced cell death: implications for vascular disease and therapy. Arterioscler Thromb Vasc Biol 2005; 20:309-316.
33. Sata M, Walsh K. Oxidized LDL activates Fas-mediated endothelial cell apoptosis. Clin Invest 2005; 102: 682-689.
34.Perlman H,Maillard L,Krasinski K,Walsh K.Evidence for the rapid onset of apoptosis in medial smooth muscle cells following balloon injury.Circulation 1997;95:981-987.
35.Kockx MM,De Meyer GR,Muhring J,Jacob W,Bult H,Herman AG.Apoptosis and related proteins in different stages of human atherosclerotic plaques.Circulation 1998;97:307-315.
36.邹飞燕,杨和平,涂玉林,杨永宗.动脉粥样硬化时平滑肌细胞凋亡的研究进展.中国动脉硬化杂志 1997;5:75-79.
37.Miyashita T,Reed JC.Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.Cell 1995;80:293-299.
38.Amura K,Chen YE,Lopez I,asaca M,Daviet L,Tamura N,Ishigami T,et al.Molecular mechanismof fibronectin gene activation by cyclic stretch in vascular smooth muscle cells.Biol Chem 2000;275:619-627.
39.KennethMY.Fibronectin peptides in cell migration and wound repair.CliniInvest 2003;105:507-509.
40.Brekken RA,Sage EH.SPARC,a matricelluar protein:at the crossroads of cell matrix communication.Matrix Biol 2004;19:816-827.
41.Jones FS,Jones PL.The tenascin family of ECM glycoproteins:structure,function,and regulation during embryonic development and tissue remodeling.Dev Dyn 2000;218:235-259.
42.Fernandez HA,Kallenbach K,Seghezzi G,Grossi E,Colvin S,Schneider R,et al.Inhibition of endothelial cell migration by gene transfer of tissue inhibitor of metalloproteinases.J Surg Res 2005; 82:156-162.
43.De Smet BJ,de Kleijn D,Hanemaaijer R,et al.Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty:a study in the atherosclerotic Yucatan micropig.Circulation 2004;101:2962-2967.
44.龚兰生,刘力生.血压昼夜变异及临床意义.中华心血管病杂志1994;2:323.
45.Imai Y,A be K,M unakataM,et al.Circadian blood pressure variation under different pathophysio logical conditions.Hypertension 1999;8:21-27.
46.Pao 1 V.P rogno stic value of ambulatory blood pressure current evidence and clinical implication.Hypertension 2000;35:844-851.
47.Michael A,Weber M,Neutel M,et al.Diagnosis of mild hypertension by ambulatory blood pressure monito ring.Circulation 1994;90:2291-2298.
48.Rizzoni D,Palombo C,Porteri E,et al.Relationships between coronary flow vasodilator capacity and small artery remodeling in hypertension patients.Hypertens 2003;21:625-631.
49.Preik M,Kelm M,Strauer BE.Management of the hypertensive patient with coronary insufficiency but without atherosclerosis.Curr Opin Cardiol 2007;18:255-259.
50.李小鹰.高血压时冠状动脉小动脉及微动脉病变的临床特点.中国病理生理杂志 2000;16:22-24.
51.史小莲,关永源.高血压发展过程中脑血管平滑肌细胞离子通道的变化.中国药理学通报 2005;21:29-32.
52.Intengan HD,Schifffin EL.Vascular remodeling in hypertension:roles of apoptosis,inflammation,and fibrosis.Hyperyension 2001;38:581-587.
53.任大宏,自发性高血压大鼠高血压前期及高血压期脑动脉的形态剂量学研究.中国循环杂志 1991;6:344-346.
54.Raizada MK,Lu D,Yang H,et al.AT_1 receptors and cellular actions of angiotensin Ⅱ in neuronal cultures of stroke prone spontaneously hypertensive rat brain.Adv Exp Med Biol 2002;396:71-78.
55.Imig JD,Inscho EW.Adaptation of the renal microcirculation to hypertension.Microcirculation 2002;9:315.
56.薛浩,刘国树.高血压肾损害及其药物治疗进展.中国药物应用与监测 2005;4:34-37.
57.Douglas P.Zipes,Peter Libby,Robort O.Bonow,Eugene Braunwald.Braunwald's Heart Disease:7~(th)edition 2007;8:907.
58.常小飞,曾衍钧,胡金麟.剪切力对血管内皮细胞内Ca~(2+)的影响及其信号传导机制.微循环学杂志 1999;9:36-38.
59.Muller JM,Chilian WM,Davis MJ.Integrin signaling transduces shear stress dependent vasodilation of coronary arterioles.Circ Res 1997;80:320-326.
60.Tomasian D,Keaney JF,Vita JA.Antioxidants and the bioactivity of endothelium-derived nitric oxide.Cardiovasc Res 2000;47:426-435.
61.Labropoulos N,Zarge J,Manaour MA,Kang SS,Baker WH,Illinois M.Compensatory arterial enlargement is a common pathobiologic response in early atherosclerosis.Am J Surg 2005;176:140-143.
62.Dzau VJ,Gibbons GH,MannM,Braun Dullaeus R.Future horizons in cardiovascular molecular therapeutics.Am J Cardiol 1997;80:33I-39I.
63.曾嵘,李进.血管平滑肌细胞增殖的有丝分裂剂研究进展.解剖科学进展 1996;2:198-203.
64.Pasterkamp G;Schoneveld AH,Hijnen DJ,de Kleijin DPV,Teepen H,vander Wal AC,et al.Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1,2 and 9in the human coronary artery.Atherosclerosis 2005;150:245-253.
65.Pasterkamp G,de Kleijin DPV,Borst C.Arterial remodeling in atherosclerosis,restenosis and after alteration of blood flow:potential mechanisms and clinical implications.Cardiovasc Res 2006;45:843-852.
66.聂如琼,王景峰,伍卫,薛迎生,张旭.损伤动脉外膜重塑和成纤维细胞表型的变化.中国动脉硬化杂志 2002;10:288-290.
67.Labinaz M,Pels K,Hoffert C,Aggarwal S,O'Brien ER.Time course and importance of neoadventitial formation in arterial remodeling following ballon angioplasty of porcine coronary arteries.Cardiovasc Res 1999;41:255-266.
68.Walsh K,Isner JM.Apoptosis in inflammatory fibropro.liferative disorders of the vessel wall.Cardiovasc Res 2000;45:756-765.
69.Mayr M,Xu Q.Smooth muscle cell apoptosis in arteriosclerosis.Exp Gerontol 2001;36:969-987.
70.Kockx MM,Herman AG.Apoptosis in atherosclerosis:beneficial or detrimental.Cardiovasc Res 2000;45:736-746.
71.Shiran A,Mintz GS,LeiboffB,Kent KM,Pichard AD,Satler LF,et al.Serial volumetric intravascular ultrasound assessment of arterial remodeling in left main coronary artery disease.Am J Cardiol 1999;83:427-432.
72.James N,Topper AA,Michael,et al.Blood flow and vascular gene exprssion,fluid shear stress as a modulator of endothelial phenotype.Mol Med Today 1995;5:40.
73.Berk BC,Abe J I,Min W,et al.endothelial atheroprotective and anti- inflammatory mechanisms.Ann N YAcad sci 2005;947:93.
74.Kaiser d,Freyberg MA,Friedl P,et al.Lack of hemodynamic forcestriggers apoptosis in vascular endothelial cell.Biochem Biophys Res Commun 2006;231:586.
75.Ohura N,Yamamoto K,Ichioka S,Sokabe T,Nakatsuka H,Baba A,Shibata M,Nakatsuka T,Harii K,Wada Y,Kohro T,Kodama T,Ando J.Global analysis of shear stress-responsive genes in vascular endothelial cells:Journal of atherosclerosis and thrombosis 2003;10:304.
76.Ishikawa Y,Asuwa N,Ishii T,Ito K,Akasaka Y,Masuda T,ZhangL,Kiguchi H.Collagen alteration in vascular remodeling by hemodynamic factors.Virchows Archiv:an international journal of pathology 2006;437:138.
77.王正荣,王玲.血管壁剪切应力系统及用于内皮细胞与白细胞粘附的研究.生物物理学报 1997;13:283.
78.Iakeda Y.Transmembrane calcium influx assiociated with von wille brandfactor binding to GPI b in the initiation of shear-induced platelet aggregation. Thromb and Hemostoas 2003; 69: 496.
2.中华人民共和国卫生部,中华人民共和国科学技术部,中华人民共和国国家统计局.中国居民营养与健康现状.中国心血管研究杂志 2004;2:19-22.
3.胡大一,贯彻循证医学的原则,做好我国心血管疾病的预防.心脏病学实践 2007 2007;1:8-18.
4.Gibbons GH,Dzau VJ.The emerging concept of vascular remodeling.N Engl J Med 1994;330:431-438.
5.Pandey N R,Benkirane K,Amiri F,et al.Effects of PPAR-γknock-down and hyperglycemia on insulin signaling in vascularsmooth muscle cells from hypertensive rats.Cardiovasc Phar-macol 2007;49:346-354.
6.Alan RO,Tara AM,Shufang QZ,et al.Hypertensive target organ damage is attenuated by a p38MAPK inhibitor:Role of systemic blood pressure and endothelial protection.Cardiovasc Res 2005;66:170-178.
7.Rizzoni D,Palombo C,Porteri E,et al.Relationships between coronary flowvasodilator capacity and small artery remodeling in hypertension patients.Hypertens 2003;21:625-631.
8. Cervenka L, Simova M, Maly J, Heller J. Role of the kidney in long-term regulation of blood pressure and the development of hypertension. Cesk Fysiol 2000; 49:116-133.
9. Hall JE, Brands MW, Henegar JR. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney.J Am Soc Nephrol 1999; 10: S258- S265.
10. Singh R, Singh AK, A lavi N, et al. Mechanism of increased angiotensin II levels in glomerular mesangial cells cultured in high glucose. J Am Soc Nephro 2003; 14: 873-880.
11. Fukai MA, Alexander RW, Akers M, et al. Angiotensin II receptor coupling to phospholipasse D is mediated by the βr subunits of heterotrimeric G_2protein in vascular smooth muscle cells. MolPharmacol 1999; 55: 142-149.
12. LI Weping, et al. Effects of atorvastatin on reactive oxygen species, expression of AT_1 receptor and p22(phox) in aorta of SHR, Clin Cardiol 2005;21: 104-108.
13. Zhong H, Alexander S, Christoph D, et al . Angiotensin II induced superoxide anion generation in human vascular endothelial cells : Role of membrane bound NADH/NADPH oxidases. Cardiovasc Res 1999; 44: 215-222.
14. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal disease. Circ Res 1998; 83:182-191.
15. Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptorgamma in vascular smooth muscle cells. Endocrinology 2001; 142: 3125-3134.
16. Diep QN, EI Mabrouk M, CohnJS, Endemann D, Amiri F, Virdis A, et al. Structure, endothelial function, cell growth, andinflammationin blood vessels of angiotension II -infused rats: role of peroxisome proliferators-activated receptor gamma. Circulation 2002; 105: 2296-2302.
17. Metcalfe BL, Huentelman MJ, Parilak LD, Taylor DG, Katovich MJ, Knot HJ, et al. Prevention of cardiac hypertrophy by angiotensin II type-2receptor gene transfer J. Hypertension 2004; 43: 1233-1238.
18. Garey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000; 35: 155-163.
19. Lassegue B, Griendling KK. Reactive oxygen species in hypertension: An update. Am J Hypertens 2004; 17: 852-860.
20. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004; 122: 339-352.
21. Owens GK, Schwartz SM. Vascular smooth muscle cell: hypertrophy and hyperploidy in the Goldblatt hypertensive rat. Circ Res 1983; 53: 491-501.
22. Snyder SH, Bredt DS. Biological role of nitric oxide. Sci Am 1992; 267: 28-35.
23. Rosendorff C. The rennin angiotensin system and vascular hypertrophy. Am Coll Cordial 1996; 28: 803-812.
24. Yu Y, Zhong MK, Li J, Sun XL, Xie GQ, Wang W, Zhu GQ. Endogenous hydrogen peroxide in paraventricular nucleus mediating cardiac sympathetic afferent reflex and regulating sympathetic activity. Pflug Arch-Eur J Physiol 2007; 454: 551-557.
25. Zhang Y, Yu Y, Zhang F et al. NAD(P)H oxidase in paraventricular nucleus contributes to the effect of angiotensin II on cardiac sympathetic afferent reflex. Brain Res 2006; 1082: 132-141.
26. Landmesser U, Cai H, Dikalov S, et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002; 40: 511-515.
27. Frenoux JM, Noirot B, Prost ED, et al. Very high alpha-tocopherol diet diminishes oxidative stress and hypercoagulation in hypertensive rats but not in normotensive rats. Med Sci M on it 2002, 8: BR401-BR407.
28. Park JB, Touyz RM, Chen X, et al. Chronic treatment with a super oxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke prone spontaneously hypertensive rats. Am J Hypertens 2002; 15: 78-84.
29. Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 2001; 89: 408-414.
30. Park YM, Park MY, Suh YL, Park JB. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun 2004; 313: 812-817.
31. Abdi A,Johns EJ. Importance of the rennin angiotensin system in the generation of kidney failure in renovascular hypertension.Hypcrtens 1996;14:1131-1137.
32.戴勇,彭武建,徐卓佳.“两肾一夹”肾性高血压大鼠模型的改进.实验动物科学与管理 2006;2:35-41.
33.杜淑旭,张春雨,金红芳,杜军保,唐朝枢.二氧化硫衍生物舒张大鼠离体主动脉血管环的效应及其机制研究.北京大学学报(医学版)2006;6:25-31.
34.徐叔云,卞如濂,陈修主编.心血管系统药物实验法.药理实验方法学(第三版,人民卫生出版社)2003;8:941-1119.
35.Ohkawa H,Ohishi N,Yagi K.Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.Anal Biochem 1979;95:351-358.
36.Han Y,Shi Z,Zhang F,Yu Y,Zhong MK,Gao XY,Wang W,Zhu GQ.Reactive oxygen species in paraventricular nucleus mediates cardiac sympathetic afferent reflex in chronic heart failure rats.Eur J Heart Fail 2007;9:967-973.
37.Gao L,Wang W,Li YL,Schultz HD,Liu D,Cornish KG;et al.Superoxide mediates sympathoexcitation in heart failure:roles of angiotensin Ⅱ and NAD(P)H oxidase.Circ Res 2004;95:937-944.
38.Latini A,Scussiato K,Rosa RB,Leipnitz G,Llesuy S,Bello-Klein A,et al.Induction of oxidative stress by L-2-hydroxyglutaric acid in rat brain.Neurosci Res 2003;74:103-110.
39.Li JM,Shah AM.Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells.Biol Chem 2002;277:52-60.
40. Li Y, Zhu H, Kuppusamy P, Roubaud V, Zweier JL, Trush MA. Validation of lucigenin (bis-N-methylacridinium) as a chemilumigenic probe for detecting superoxide anion radical production by enzymatic and cellular systems. Biol Chem 1998; 273: 2015-2023.
41. Tai MH, Wang LL, Wu KL, Chan JY. Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Radic Biol Med 2005; 38: 450-462.
42. Dzau VJ, Gibbons GH, Morishita R, Pratt RE. New perspectives in hypertention research: potentials of vascular biology. Hypertention 1994; 23: 132-140.
43. Dzau VJ. Theodore cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047-1052.
44. Han Y, Runge MS, Brasier AR. Angiotensin II induces interleukin6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res 1999; 84: 695-703.
45. Reddan JR, Sevilla MD, Giblin FJ, et al. The superoxide dismutase mimic TEMPOL protects cultured rabbit lens epithelial cells from hydrogen peroxide insult. Exp Eye Res 1993; 56: 543-554.
46. Puri PL, Avantaggiati ML, Burgio VL, et al. Reactive oxygen intermediates (ROIs) are involved in the intracellular transduction of angiotensin II signal in C2C12 cells. Ann N Y Acad Sci 1995; 752: 394-405.
47. Sun C, Sellers KW, Sumners C, Raizada MK. NAD(P)H Oxidase Inhibition Attenuates Neuronal Chronotropic Actions of Angiotensin II. Circ Res 2005; 96: 659-666.
48. Akpaffiong MJ, Taylor AA. Antihypertensive and vesodiolator actions of antioxidants in SHR. Am J Hpertension 1998; 11: 1450-1460.
49. Koska J, Syrova D, Blazicek P, et al Malondialdehyele, lipofuscin and activity of antioxidant enzymes during physical exercise in patients with essential hypertension. Hypertensions 1999; 17: 529-535.
50. Greenstock CL, Miller RW. The oxidation of tiron by superoxide anion: Kinetics of the reaction in aqueous solution in chloroplasts. Biochim Biophys Acta 1975; 396: 11-16.
51. Yamada J, Yoshimura S, Yamakawa H, et al. Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation. Neurosci Res 2003; 45(1): 1-8.
52. Guzik TJ, Olszanecki R, Sadowski J et al. Superoxide dismutase activity and expression in human venous and arterial bypass graft vessels. Physiol Pharmacol 2005; 56: 313-323.
53. Pryor WA, Godber SS. Noninvasive measures of oxidative stress status in humans. Free Radic Biol Med 1991; 10: 177-184.
54. Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest 1982; 47: 412-426.
55. Müunzel T, Kurz S, Thoenes Rajagoplalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane bound NADH oxidase: A new action for an old drug. Clin Invest 1996; 98: 1465-1470.
56. Stolk J, Hiltermann TJ, Dijkman JH, Verhoeven AJ. Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Bio 1994; 11:95-102.
57. Ben Shaul V, Lomnitski L, Nyska A, et al. The effect of natural antioxidants NAO and apocynin on oxidative stress in the rat heart following LPS challenge. Toxicol Lett 2001; 123: 1-10.
58. Dodd O, Pearse DB. Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury. Am J Physiol Heart Circ Physiol 2000; 279: H303-H312.
59. Kazama K, Anrather J, Zhou P, et al. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 2004; 95: 1019-1026.
60. Souza HP, Cardounel AJ, Zweier JL. Mechanisms of free radical production in the vascular wall. Coron Artery Dis 2003; 14: 101-107.
61. Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003; 24: 471-478.
62. Zekry D, Epperson TK, Krause KH. A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia? IUBMB Life 2003; 55: 307-313.
63. Knapp LT, Klann E. Role of reactive oxygen species in hippocampal long-term potentiation: contributory or inhibitory? Neurosci Res 2002; 70: 1-7.
64. Suzukawa K, Miura K, Mitsushita J, et al. Nerve growth factor-induced neuronal differentiation requires generation of Racl-regulated reactive oxygen species. Biol Chem 2000; 275: 13175-13178.
65. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000; 86: 494-501.
66. Li JM, Shah AM. Mechanism of endothelial cell NADPH oxidase activation by angiotensin II: Role of the p47(phox) subunit. Biol Chem 2003; 278: 12094-12100.
67. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of agp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002; 105: 293-296.
68. Cifuentes ME, Rey FE, Carretero OA, Pagano PJ. Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin Il-infused mice. Am J Physiol Heart Circ Physiol 2000; 279: H2234-H2240.
69. Zimmerman MC, Dunlay RP, Lazartigues E, et al. Requirement for Racl-Dependent NADPH Oxidase in the Cardiovascular and Dipsogenic Actions of Angiotensin II in the Brain. Circ Res 2004; 95: 532-539.
70. Zhong H, Alexander S, Christoph D, et al. Angiotensin II induced superoxide anion generation in human vascular endothelial cells: Role of membrane bound NADH/NADPH oxidases. Cardiovasc Res 1999; 44: 215-222.
71. Karthikeyan VJ, Lip GY. Oxidative stress and hypertension. Int J Clin Pract 2006; 60: 1525-1527.
1.Chobanian AV,Bakris GL,Black HR,Cushman WC,Green LA,Izzo JL,Jones DW,Materson BJ,Oparil S,Wright JT,Toccella EJ.Seventh Report of the Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure.Hypertension 2003;42:1206-1252.
2.Gibbons GH,Dzau VJ.The emerging concept of vascular remodeling.N Engl J Med 1994;330:431-438.
3.Alan RO,Tara AM,Shufang QZ,et al.Hypertensive target organ damage is attenuated by a p38MAPK inhibitor:Role of systemic blood pressure and endothelial protection.Cardiovasc Res 2005;66:170-178.
4.王凡,刘国树.大动脉顺应性减退的机制研究.国外医学:心血管疾病分册 2005;32:275-278.
5.董现峰,洪华山.心血管病时冠状动脉微血管重构研究进展.中国动脉硬化杂志 2004;12:116-120.
6.Dzau VJ,Gibbons GH,Morishita R,Pratt RE.New perspectives in hypertention research:potentials of vascular biology.Hypertention 2004;23:132-140.
7.Fujii K,Umemoto S,Fujii A,et al.Angiotens in Ⅱ type 1receptorantagonis t downregulates nonmuscle myos in heavy chains in spontaneously hypertensive rat aorta.Hypertension 1999;33:975-980.
8.秦旭平,龙光,徐立朋,等.氯沙坦和培哚普利逆转高血压大鼠 心血管重构的比较.中国药理学通报 2004;20:1107-1111.
9.李留东,廖玉华,周子华,等.主动免疫AT_1受体对自发性高血压大鼠血管重构的影响.高血压杂志 2005;13:296-300.
10.Malek AM,Alper SL,Izumo S.Hemodynamic shear stress and its role in atherosclerosis.JAMA 1999;282:2035-2042.
11.Langille BL.Blood flow induced remodeling of the artery wall[A].In:Bevan JA,Kaley G,Rubanyi G,eds:Flow dependent regulation of vascular function.New York NY:Coxford 2005;2:277-299.
12.Barbee KA,Mundel T,Lal R,et al.Subcellular distribution of shear stress at the surface of flow2aligned and nonaligned endothelial monolayers.Am J Physiol 2002;268:H1765-H1772.
13.Kanai AJ,Strauss HC,Truskey GA,et al.Shear stress induces ATP in dependent transient cells,measureddirectly from vacular endothelialcells,measured directly with a porphyrinic microsensor.Circ Res 2003;77:284-293.
14.Fukai T,Siegfried MR,Ushio Fukai M,et al.Modulation of extracellular superoxide dismutase expression by angiotensin Ⅱ and hypertension.Circ Res 1999;85:23-28.
15.Somers MJ,Mavromatis K,Galis ZS,et al.Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt.Circulation 2000;101:1722-1728.
16.Han Y,RungeMS,BrasierAR.Angiotensin Ⅱ induces interleukin-6transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor kappa B transcription factors.Circ Res 1999;84:695-703.
17. Lingyun W, Jacques DC. Effect of superoxide on signaling pathways in smooth muscle cells from rats. Hypertension 1999; 34:247-253.
18. Rosendorff C. The rennin angiotensin system and vascular hypertrophy. J Am Coll Cordial 1996; 28: 803-812.
19. Berry C, Humilton CA, brosonan MJ, et al. Investigation into the sources of superoxide in human blood vessels Angioten II increase superoxide production in human internal mammary arteries. Circulation 2000; 101: 2206-2212.
20. Fukai MA, Alexander RW, Akers M, et al. Angiotensin II receptor coupling to phospholipasse D is mediated by the βr subunits of heterotrimeric G-protein in vascular smooth muscle cells. MoP harmacol 1999; 55: 142-149.
21. Touyz RM, Schiffrin EL. Ang II -stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension 1999; 34: 976-982.
22. Knauss TC, Jaffer FE, Abboud HE. Phosphatidic acid modulates DNA synthesis, phospholipase C and platelet derived growth factor mRNAs in cultured mesangial cells. Biol Chem 1990; 265: 14457-144631.
23. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186-195.
24. Arangino S, et al. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol 2003;83: 1417-1419.
25. Cagnacci A. Melatonin in relation to physiology in adult humans. Pineal Res 1999; 21: 200-213.
26. Skalak TC, Price RJ. The role of mechanical stress is in microvascular remodeling. Microcirculation 1996; 3: 143-165.
27. Gerber HP, McMurtrey A, Kowalski J, Yan MH, Keyt BA, Dixit V, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'2 kinase Akt signal transduction pathway: requirement for Flk21/ KDR activation. Biol Chem 1998; 273: 336-343.
28. Fukuo K, Hata S , Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, et al. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 2000; 27: 823-826.
29. Nicholson DW, Thornberry NA. Caspases killer proteases. Trends Biochem Sci 1997; 22: 299-306.
30. Pollman MJ, Naumovski L, Gibbons GH. Vascular cell apoptosis: Cell type specific modulation by transforming growth factor β1 in endothelial cells versus smooth muscle cells. Circulation 1999; 99: 019-026.
31. Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 449-456.
32. Sata M, Suhara T, Walsh K. Vascular endothelial cells and smooth muscle cells differ in their expression of Fas and Fas ligand and in their sensitivity to Fasligand-induced cell death: implications for vascular disease and therapy. Arterioscler Thromb Vasc Biol 2005; 20:309-316.
33. Sata M, Walsh K. Oxidized LDL activates Fas-mediated endothelial cell apoptosis. Clin Invest 2005; 102: 682-689.
34.Perlman H,Maillard L,Krasinski K,Walsh K.Evidence for the rapid onset of apoptosis in medial smooth muscle cells following balloon injury.Circulation 1997;95:981-987.
35.Kockx MM,De Meyer GR,Muhring J,Jacob W,Bult H,Herman AG.Apoptosis and related proteins in different stages of human atherosclerotic plaques.Circulation 1998;97:307-315.
36.邹飞燕,杨和平,涂玉林,杨永宗.动脉粥样硬化时平滑肌细胞凋亡的研究进展.中国动脉硬化杂志 1997;5:75-79.
37.Miyashita T,Reed JC.Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.Cell 1995;80:293-299.
38.Amura K,Chen YE,Lopez I,asaca M,Daviet L,Tamura N,Ishigami T,et al.Molecular mechanismof fibronectin gene activation by cyclic stretch in vascular smooth muscle cells.Biol Chem 2000;275:619-627.
39.KennethMY.Fibronectin peptides in cell migration and wound repair.CliniInvest 2003;105:507-509.
40.Brekken RA,Sage EH.SPARC,a matricelluar protein:at the crossroads of cell matrix communication.Matrix Biol 2004;19:816-827.
41.Jones FS,Jones PL.The tenascin family of ECM glycoproteins:structure,function,and regulation during embryonic development and tissue remodeling.Dev Dyn 2000;218:235-259.
42.Fernandez HA,Kallenbach K,Seghezzi G,Grossi E,Colvin S,Schneider R,et al.Inhibition of endothelial cell migration by gene transfer of tissue inhibitor of metalloproteinases.J Surg Res 2005; 82:156-162.
43.De Smet BJ,de Kleijn D,Hanemaaijer R,et al.Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty:a study in the atherosclerotic Yucatan micropig.Circulation 2004;101:2962-2967.
44.龚兰生,刘力生.血压昼夜变异及临床意义.中华心血管病杂志1994;2:323.
45.Imai Y,A be K,M unakataM,et al.Circadian blood pressure variation under different pathophysio logical conditions.Hypertension 1999;8:21-27.
46.Pao 1 V.P rogno stic value of ambulatory blood pressure current evidence and clinical implication.Hypertension 2000;35:844-851.
47.Michael A,Weber M,Neutel M,et al.Diagnosis of mild hypertension by ambulatory blood pressure monito ring.Circulation 1994;90:2291-2298.
48.Rizzoni D,Palombo C,Porteri E,et al.Relationships between coronary flow vasodilator capacity and small artery remodeling in hypertension patients.Hypertens 2003;21:625-631.
49.Preik M,Kelm M,Strauer BE.Management of the hypertensive patient with coronary insufficiency but without atherosclerosis.Curr Opin Cardiol 2007;18:255-259.
50.李小鹰.高血压时冠状动脉小动脉及微动脉病变的临床特点.中国病理生理杂志 2000;16:22-24.
51.史小莲,关永源.高血压发展过程中脑血管平滑肌细胞离子通道的变化.中国药理学通报 2005;21:29-32.
52.Intengan HD,Schifffin EL.Vascular remodeling in hypertension:roles of apoptosis,inflammation,and fibrosis.Hyperyension 2001;38:581-587.
53.任大宏,自发性高血压大鼠高血压前期及高血压期脑动脉的形态剂量学研究.中国循环杂志 1991;6:344-346.
54.Raizada MK,Lu D,Yang H,et al.AT_1 receptors and cellular actions of angiotensin Ⅱ in neuronal cultures of stroke prone spontaneously hypertensive rat brain.Adv Exp Med Biol 2002;396:71-78.
55.Imig JD,Inscho EW.Adaptation of the renal microcirculation to hypertension.Microcirculation 2002;9:315.
56.薛浩,刘国树.高血压肾损害及其药物治疗进展.中国药物应用与监测 2005;4:34-37.
57.Douglas P.Zipes,Peter Libby,Robort O.Bonow,Eugene Braunwald.Braunwald's Heart Disease:7~(th)edition 2007;8:907.
58.常小飞,曾衍钧,胡金麟.剪切力对血管内皮细胞内Ca~(2+)的影响及其信号传导机制.微循环学杂志 1999;9:36-38.
59.Muller JM,Chilian WM,Davis MJ.Integrin signaling transduces shear stress dependent vasodilation of coronary arterioles.Circ Res 1997;80:320-326.
60.Tomasian D,Keaney JF,Vita JA.Antioxidants and the bioactivity of endothelium-derived nitric oxide.Cardiovasc Res 2000;47:426-435.
61.Labropoulos N,Zarge J,Manaour MA,Kang SS,Baker WH,Illinois M.Compensatory arterial enlargement is a common pathobiologic response in early atherosclerosis.Am J Surg 2005;176:140-143.
62.Dzau VJ,Gibbons GH,MannM,Braun Dullaeus R.Future horizons in cardiovascular molecular therapeutics.Am J Cardiol 1997;80:33I-39I.
63.曾嵘,李进.血管平滑肌细胞增殖的有丝分裂剂研究进展.解剖科学进展 1996;2:198-203.
64.Pasterkamp G;Schoneveld AH,Hijnen DJ,de Kleijin DPV,Teepen H,vander Wal AC,et al.Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1,2 and 9in the human coronary artery.Atherosclerosis 2005;150:245-253.
65.Pasterkamp G,de Kleijin DPV,Borst C.Arterial remodeling in atherosclerosis,restenosis and after alteration of blood flow:potential mechanisms and clinical implications.Cardiovasc Res 2006;45:843-852.
66.聂如琼,王景峰,伍卫,薛迎生,张旭.损伤动脉外膜重塑和成纤维细胞表型的变化.中国动脉硬化杂志 2002;10:288-290.
67.Labinaz M,Pels K,Hoffert C,Aggarwal S,O'Brien ER.Time course and importance of neoadventitial formation in arterial remodeling following ballon angioplasty of porcine coronary arteries.Cardiovasc Res 1999;41:255-266.
68.Walsh K,Isner JM.Apoptosis in inflammatory fibropro.liferative disorders of the vessel wall.Cardiovasc Res 2000;45:756-765.
69.Mayr M,Xu Q.Smooth muscle cell apoptosis in arteriosclerosis.Exp Gerontol 2001;36:969-987.
70.Kockx MM,Herman AG.Apoptosis in atherosclerosis:beneficial or detrimental.Cardiovasc Res 2000;45:736-746.
71.Shiran A,Mintz GS,LeiboffB,Kent KM,Pichard AD,Satler LF,et al.Serial volumetric intravascular ultrasound assessment of arterial remodeling in left main coronary artery disease.Am J Cardiol 1999;83:427-432.
72.James N,Topper AA,Michael,et al.Blood flow and vascular gene exprssion,fluid shear stress as a modulator of endothelial phenotype.Mol Med Today 1995;5:40.
73.Berk BC,Abe J I,Min W,et al.endothelial atheroprotective and anti- inflammatory mechanisms.Ann N YAcad sci 2005;947:93.
74.Kaiser d,Freyberg MA,Friedl P,et al.Lack of hemodynamic forcestriggers apoptosis in vascular endothelial cell.Biochem Biophys Res Commun 2006;231:586.
75.Ohura N,Yamamoto K,Ichioka S,Sokabe T,Nakatsuka H,Baba A,Shibata M,Nakatsuka T,Harii K,Wada Y,Kohro T,Kodama T,Ando J.Global analysis of shear stress-responsive genes in vascular endothelial cells:Journal of atherosclerosis and thrombosis 2003;10:304.
76.Ishikawa Y,Asuwa N,Ishii T,Ito K,Akasaka Y,Masuda T,ZhangL,Kiguchi H.Collagen alteration in vascular remodeling by hemodynamic factors.Virchows Archiv:an international journal of pathology 2006;437:138.
77.王正荣,王玲.血管壁剪切应力系统及用于内皮细胞与白细胞粘附的研究.生物物理学报 1997;13:283.
78.Iakeda Y.Transmembrane calcium influx assiociated with von wille brandfactor binding to GPI b in the initiation of shear-induced platelet aggregation. Thromb and Hemostoas 2003; 69: 496.