高盐饮食对Wistar大鼠血压和颈动脉重塑的影响及替米沙坦干预
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摘要
目的：研究高盐饮食对Wistar大鼠颈动脉重塑的影响及替米沙坦的干预作用。
方法：60只Wistar大鼠,随机分为正常盐对照组(0.5%Nacl),8%高盐模型组和8%高盐+替米沙坦干预组,每两周测量尾动脉压一次,喂养共24周。实验结束后,根据尾动脉血压又将8%高盐模型组分为高盐高血压组和高盐血压正常组。大鼠给予麻醉后取颈总动脉,进行固定、包埋,切片行苏木素-伊红染色(HE)染色,利用计算机辅助系统测量颈动脉中膜厚度(MT)、腔径(LD)及中膜厚度与腔径的比值(MT/LD); Masson染色测胶原纤维面积百分比；免疫组化染色检测颈动脉α-平滑肌肌动蛋白(a-SMA)、增殖细胞核抗原(PCNA)、转化生长因子-β1(TGF-β1)、smad2/3、smad7、血管紧张素Ⅱ(AngⅡ)、血管紧张素Ⅱ1型受体(AT1)、血管紧张素Ⅱ2型受体(AT2)等在颈动脉中膜的表达；放射免疫法测定颈动脉和肾上腺组织醛固酮的含量、肾上腺、下丘脑和血液中内源性哇巴因(EO)的含量。
结果：(1)实验开始第7周,高盐高血压组的尾动脉血压明显高于其他三个组(P<0.05),并持续到实验结束；第24周,高盐高血压组颈动脉测压也明显高于其他三个组(P<0.05)；除高盐高血压组外,其他三组的血压尾动脉和颈动脉测压均无统计学差异。(2)经a-SMA鉴定,颈动脉中膜为血管平滑肌细胞。高盐高血压组和高盐血压正常组颈动脉中膜的MT、MT/LD、PI、胶原纤维面积百分比均明显高于对照组(P<0.01),而替米沙坦组的MT、MT/LD>PI、胶原纤维面积百分比均明显降低(P<0.01)。(3)高盐高血压组和高盐血压正常组颈动脉中膜的smad2/3表达明显高于对照组(P<0.01),而干预组明显降低(P<0.01),高盐高血压组TGF-β1表达亦高于高盐血压正常组) smad7在对照组颈动脉中膜表达均高于其他三组(P<0.01),干预组smad7表达明显高于高盐高血压组和高盐血压正组(P<0.01)。(4)各组间颈动脉中膜AngⅡ表达均无差异(P>0.05),高盐高血压组和高盐血压正常组颈动脉中膜AT1表达均明显高于对照组和干预组(P<0.01),高盐高血压组颈动脉中膜AT2表达均明显高于其他三个组(P<0.01),与对照组相比,高盐血压正常组和干预组AT2表达亦明显升高(P<0.01)；高盐高血压组颈动脉中膜醛固酮含量高于对照组和高盐血压正常组(P<0.05),显著高于干预组(P<0.01),对照组肾上腺醛固酮含量均明显高于其他三个组(P<0.01),肾上腺、下丘脑和血液中EO含量各组间均无差异。
结论：(1)长期高盐饮食可直接或间接(血压升高)导致颈动脉重塑,其结构特征为动脉中膜增厚、血管平滑肌增殖和胶原沉积。(2)高盐诱导颈动脉重构的机制可能与TGF-β1/smads信号转导中的正性和负性调控及组织局部RAAS组分(AT1、AT2)上调有关,其中组织醛固酮生成增加和TGF-β1表达上调可能是高盐诱导高血压和颈动脉重构的主要机制。(3)替米沙坦能抑制血管平滑肌增生和胶原堆积、阻止高盐诱导的高血压和颈动脉重构,其药理学机制可能是抑制局部RAAS和调节TGF-β1/smads信号通路。
Objective:To study the influence of high salt diet on blood pressure and carotid artery remodeling and the intervention of telmisartan in Wiatar rats.
Methods:60 Wistar rats were fed a normal salt diet(NSD:0.5%NaCl), high salt diet(HSD:8% NaCl), or HSD+Telmisartan until 24 weeks, tail-cuff blood pressure were measured every two weeks. After the end of experiment, HSD group was divided into hypertension group (HHBp) and normal blood pressure group(HNBp) according of the tail-cuff blood pressure. Media thickness (MT), lumen diameter (LD), media thickness and lumen diameter ratio (MT/LD) and collagen fiber area percentage of carotid arteries were measured. The expression of a-smooth muscle actin(a-SMA), TGF-β1,smad2/3, smad7,AngⅡ,AT1,AT2 and PCNA in media of carotid arteries were measured by immunohistochemistry. Aldosterone in vessel and adrenal gland was mesured by radioimunoassay. The endogenous ouabain (EO) in adrenal gland、hypothalamus and the blood was mesured by radioimunoassay.
Results:(1)At 7 week of experiments, tail-cuff blood pressure in HHBp group was much higher than that in other three groups (P<0.05), and continued to experiment ends. At 24 week, carotid artery pression in HHBp group was also much higher than in other three groups (P< 0.05).Tail-cuff blood pressure and carotid arteries pression were not statistically significant in the other three groups. (2) MT, MT/LD、PI、collagen fiber area percentage of carotid arteries in HHBp and HNBp groups were higher than those in the control group (P< 0.01), and MT, MT/LD、PI、collagen fiber area percentage in HSD+ telmisartan group were much lower (P< 0.01). (3) TGF-β1, smad2/3 of carotid arteries media in HHBp and HNBp groups were higher than in the control group (P< 0.01), and in telmisartan group were much lower (P< 0.01). smad7 of carotid arteries media in control group was much higher than in other three groups (P< 0.01), in telmisartan group were much higher than in HHBp and HNBp groups (P< 0.01).(4) AngⅡof carotid artery was no difference in each group. AT1 expression of carotid arteries media in HHBp and HNBp groups were higher than in the control group (P< 0.01). and were much lower in telmisartan group (P< 0.01). The expression of AT2 in carotid arteries media in HHBp were higher than in other three groups (P< 0.01).AT2 of carotid arteries media in HHBp and telmisartan group were higher than in the control group (P< 0.01). But aldosterone level in carotid arteries media were higher in HNBp groups than the control group (P< 0.05), much higher than in telmisartan group (P< 0.01). Aldosterone level in adrenal gland were higher than in other three groups (P< 0.01).EO level in adrenal gland、hypothalamus and the blood were no differences among all groups.
Conclusion:(1)Long-term high-salt diet can cause the carotid artery remodeling directly or through high blood pressure, the structure is characterized by medial thickening, vascular smooth muscle cell proliferation and collagen deposition.(2) High salt-induced carotid artery remodeling may be related to positive and negative regulation of signal transduction in TGF-(31/smads and the upregulation of RAAS components (ATI, AT2) in local tissues, increased aldosterone and TGF-β1 upregulation may be the main mechanism in high salt-induced hypertension and carotid artery remodeling.(3) Telmisartan can inhibit proliferation of vascular smooth muscle cells and collagen accumulation, and prevent high salt-induced hypertension and remodeling of carotid artery, its pharmacological mechanism may be inhibiting the local RAAS and regulating TGF-β1/smads signaling pathways.
方法：60只Wistar大鼠,随机分为正常盐对照组(0.5%Nacl),8%高盐模型组和8%高盐+替米沙坦干预组,每两周测量尾动脉压一次,喂养共24周。实验结束后,根据尾动脉血压又将8%高盐模型组分为高盐高血压组和高盐血压正常组。大鼠给予麻醉后取颈总动脉,进行固定、包埋,切片行苏木素-伊红染色(HE)染色,利用计算机辅助系统测量颈动脉中膜厚度(MT)、腔径(LD)及中膜厚度与腔径的比值(MT/LD); Masson染色测胶原纤维面积百分比；免疫组化染色检测颈动脉α-平滑肌肌动蛋白(a-SMA)、增殖细胞核抗原(PCNA)、转化生长因子-β1(TGF-β1)、smad2/3、smad7、血管紧张素Ⅱ(AngⅡ)、血管紧张素Ⅱ1型受体(AT1)、血管紧张素Ⅱ2型受体(AT2)等在颈动脉中膜的表达；放射免疫法测定颈动脉和肾上腺组织醛固酮的含量、肾上腺、下丘脑和血液中内源性哇巴因(EO)的含量。
结果：(1)实验开始第7周,高盐高血压组的尾动脉血压明显高于其他三个组(P<0.05),并持续到实验结束；第24周,高盐高血压组颈动脉测压也明显高于其他三个组(P<0.05)；除高盐高血压组外,其他三组的血压尾动脉和颈动脉测压均无统计学差异。(2)经a-SMA鉴定,颈动脉中膜为血管平滑肌细胞。高盐高血压组和高盐血压正常组颈动脉中膜的MT、MT/LD、PI、胶原纤维面积百分比均明显高于对照组(P<0.01),而替米沙坦组的MT、MT/LD>PI、胶原纤维面积百分比均明显降低(P<0.01)。(3)高盐高血压组和高盐血压正常组颈动脉中膜的smad2/3表达明显高于对照组(P<0.01),而干预组明显降低(P<0.01),高盐高血压组TGF-β1表达亦高于高盐血压正常组) smad7在对照组颈动脉中膜表达均高于其他三组(P<0.01),干预组smad7表达明显高于高盐高血压组和高盐血压正组(P<0.01)。(4)各组间颈动脉中膜AngⅡ表达均无差异(P>0.05),高盐高血压组和高盐血压正常组颈动脉中膜AT1表达均明显高于对照组和干预组(P<0.01),高盐高血压组颈动脉中膜AT2表达均明显高于其他三个组(P<0.01),与对照组相比,高盐血压正常组和干预组AT2表达亦明显升高(P<0.01)；高盐高血压组颈动脉中膜醛固酮含量高于对照组和高盐血压正常组(P<0.05),显著高于干预组(P<0.01),对照组肾上腺醛固酮含量均明显高于其他三个组(P<0.01),肾上腺、下丘脑和血液中EO含量各组间均无差异。
结论：(1)长期高盐饮食可直接或间接(血压升高)导致颈动脉重塑,其结构特征为动脉中膜增厚、血管平滑肌增殖和胶原沉积。(2)高盐诱导颈动脉重构的机制可能与TGF-β1/smads信号转导中的正性和负性调控及组织局部RAAS组分(AT1、AT2)上调有关,其中组织醛固酮生成增加和TGF-β1表达上调可能是高盐诱导高血压和颈动脉重构的主要机制。(3)替米沙坦能抑制血管平滑肌增生和胶原堆积、阻止高盐诱导的高血压和颈动脉重构,其药理学机制可能是抑制局部RAAS和调节TGF-β1/smads信号通路。
Objective:To study the influence of high salt diet on blood pressure and carotid artery remodeling and the intervention of telmisartan in Wiatar rats.
Methods:60 Wistar rats were fed a normal salt diet(NSD:0.5%NaCl), high salt diet(HSD:8% NaCl), or HSD+Telmisartan until 24 weeks, tail-cuff blood pressure were measured every two weeks. After the end of experiment, HSD group was divided into hypertension group (HHBp) and normal blood pressure group(HNBp) according of the tail-cuff blood pressure. Media thickness (MT), lumen diameter (LD), media thickness and lumen diameter ratio (MT/LD) and collagen fiber area percentage of carotid arteries were measured. The expression of a-smooth muscle actin(a-SMA), TGF-β1,smad2/3, smad7,AngⅡ,AT1,AT2 and PCNA in media of carotid arteries were measured by immunohistochemistry. Aldosterone in vessel and adrenal gland was mesured by radioimunoassay. The endogenous ouabain (EO) in adrenal gland、hypothalamus and the blood was mesured by radioimunoassay.
Results:(1)At 7 week of experiments, tail-cuff blood pressure in HHBp group was much higher than that in other three groups (P<0.05), and continued to experiment ends. At 24 week, carotid artery pression in HHBp group was also much higher than in other three groups (P< 0.05).Tail-cuff blood pressure and carotid arteries pression were not statistically significant in the other three groups. (2) MT, MT/LD、PI、collagen fiber area percentage of carotid arteries in HHBp and HNBp groups were higher than those in the control group (P< 0.01), and MT, MT/LD、PI、collagen fiber area percentage in HSD+ telmisartan group were much lower (P< 0.01). (3) TGF-β1, smad2/3 of carotid arteries media in HHBp and HNBp groups were higher than in the control group (P< 0.01), and in telmisartan group were much lower (P< 0.01). smad7 of carotid arteries media in control group was much higher than in other three groups (P< 0.01), in telmisartan group were much higher than in HHBp and HNBp groups (P< 0.01).(4) AngⅡof carotid artery was no difference in each group. AT1 expression of carotid arteries media in HHBp and HNBp groups were higher than in the control group (P< 0.01). and were much lower in telmisartan group (P< 0.01). The expression of AT2 in carotid arteries media in HHBp were higher than in other three groups (P< 0.01).AT2 of carotid arteries media in HHBp and telmisartan group were higher than in the control group (P< 0.01). But aldosterone level in carotid arteries media were higher in HNBp groups than the control group (P< 0.05), much higher than in telmisartan group (P< 0.01). Aldosterone level in adrenal gland were higher than in other three groups (P< 0.01).EO level in adrenal gland、hypothalamus and the blood were no differences among all groups.
Conclusion:(1)Long-term high-salt diet can cause the carotid artery remodeling directly or through high blood pressure, the structure is characterized by medial thickening, vascular smooth muscle cell proliferation and collagen deposition.(2) High salt-induced carotid artery remodeling may be related to positive and negative regulation of signal transduction in TGF-(31/smads and the upregulation of RAAS components (ATI, AT2) in local tissues, increased aldosterone and TGF-β1 upregulation may be the main mechanism in high salt-induced hypertension and carotid artery remodeling.(3) Telmisartan can inhibit proliferation of vascular smooth muscle cells and collagen accumulation, and prevent high salt-induced hypertension and remodeling of carotid artery, its pharmacological mechanism may be inhibiting the local RAAS and regulating TGF-β1/smads signaling pathways.
引文
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4.于茜,钟久昌,等.RAS系统、血管重塑与高血压[J].心脑血管病防治,2010,10(1):58-59
5.曾昭华,Robert M.K,罗碧辉,等.一种新的高盐致高血压动物模型及其血管重构改变[J].中国临床药理学与治疗学,2005,10：24-28.
6.陈宏,洪华山等.替米沙坦对自发性高血压大鼠颈动脉重构的影响[J].实用医学杂志2007,23(23)：3665-3667.
7.胡威,商黔惠,姜黔峰,等.依那普利、厄贝沙坦单用和联用对高血压大鼠主动脉重塑与中膜钠泵及钙泵的影响[J].中华高血压杂志,2010,18(6)：528-531.
8.郭慧君,王知佳.中医药干预高血压病血管重构的研究进展[J].中西医结合心脑血管病杂志2010,8(4)：472-474.
9.陈宏,洪华山.自发性高血压大鼠颈动脉的重构—替米沙坦的干预实验[D].福建,福建医科大学,2007.
10. GrandAM, MarescaAM. Blockade of the rennin-angiotensin-aldosterone system:effects on hypertensive target organ damage. Cardiovasc Hematol Agents Med chem.2006,4:219-228
11. Carey RM. Update oil the role of the AT2 receptor. Curr Opin Nephml Hypertens, 2005,14(1):67-71.
12.王献民ACEI及ATl受体拮抗剂干预肺切除加野百合碱诱导大鼠肺动脉高压肺血管重构作用机制研究[D].四川,四川大学,2007.
13.杨宇,陈灿.肾素-血管紧张素系统与高血压血管重构关系研究进展[J].医学综述,2008,14(13)：1941-1943.
14. Schiffrin EL,Touyz RM. From bedside to bench to bedside:role of rennin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension.AmJ Physiol Heart Physiol.2004;287:435-447.
15. Mulvary MJ. Small artery remodeling and significance in the development of hypertension. News physiol Sci.2002;17:105-109
16. Kim S,Iwaok H. molecular and cellar mechamisms of angiotensin Ⅱ mediated cardiovascual and renal disease. Pharmacol Rew.2001;52:11-34
17. Ruperez M,Lorenzo O. Blanco-colio L,etal. Angiotensin Ⅱ increase connective tissue growth factor in vascular smooth muscle cells. J hypertens 2001;19(5):17-18
18. Nat han C. Points of control in inflammation. Nature,2002.420:846-853.
19. Touyz RM, Tabet F, Schiff rin EL. Redox2dependent signallingby angiotensin Ⅱ and ascular remodelling in hypertensionClin Exp Pharmacol Physiol,2003,30:860-866
20.赵丽,张翥.AngⅡ介导的高血压炎症反应机制[J].高血压杂志,2005,13(9)：533-535.
21. Lee EY, Shim MS, Kim MJ, et al. angiotensin Ⅱ receptor blocker attenuates overexpression of vascular endot helial growt h factor in diabetic podocytes. Exp Mol Med,2004,36:65-70
22.赵蕾.RAS各组分的基因在SHR心、肾、主动脉中的表达及意义[D].上海,第二军医大学.2007.
23.王超.醛固酮增多症大鼠血管重构发生机制的实验研究[D].武汉,华中科技大学.2009.
24.刘云涛.醛固酮对心血管的影响[J].当代医学,2009,21(176)：19-21.
25.张媛,孙跃民等.原发性高血压大鼠醛固酮与血管重构关系及依普利酮的治疗作用.中国慢性病预防与控制2009,17(5)：490-492.
26.周定.SHRs醛固酮水平对肾脏纤维化与CD2AP的影响和依普利酮的作用[D].天津,天津医科大学.2009.
27. Delopone E,Caballro R, etal. Angitotensin Ⅱ, angitotensin Ⅱ,antagonists and spirnolactone and their modulation of cardiac repolarization. Trends parmacol Sci 2005;26(3);155-61.
28. Jaffe LZ, Mendelsohn ME. Angitotensin Ⅱ and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res.2005;196(16):643-50.
29. Gresner A M, Weiskircben R,etal. Role of TGF-beta in hepatic-fibrosis [j] Front BioSci,2002,7:793-807.
30.李征,李茹香,等.MMP-9与TGF-β1在高血压血管重构中的作用及阿托伐他汀的干预研究[J].中国药物与临床,2008,8(2)：113-115.
31.陈宏,马建芳.替米沙坦对自发性高血压大鼠颈动脉Ⅰ型、Ⅲ型胶原及转化生长因子-β1表达的影响[J].中国误诊学杂志,2009,9(2)：256-259.
32.左江伟,覃晓.转化生长因子-β1在动脉钙化中的表达和意义[D].广西,广西医科大学.2007.
33.王伟伟,孙跃民,等.依普利酮改善自发性高血压大鼠血管重构与降压无关[J].中华高血压杂志,2009,17(10)：912-916.
34.王立文,刘光耀,胡渝生,等.血管紧张素Ⅱ和转化生长因子p在两肾一夹高血压大鼠血管重构中的作用[J].中国心血管杂志,2003,8(2)：83-88.
35.赵晓燕苏金林,等.TGF-β/Smads信号通路在心血管重构中的作用研究进展[J]。河北医药2010,32(17)：2415-2417.
36.闫承慧,申景等.血管平滑肌细胞增殖与转化生长因子p/Smads的表达[J].中国临床康复,2005,9(19)：50-52.
37. Itoh S,Itoh F,Goumans MJ,et al.Signaling of transforming growth factor-beta family members through Smad proteins.Eur J Biochem,2000 (24):6954-6767
38.徐梦丹,戴秋艳,等.氯沙坦和替米沙坦保护靶器官与抑制单核细胞趋化蛋白1及受体2表达有关[J].中华高血压杂志,2007,15(9)：735-740.
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