天麻舒心方对自发性高血压大鼠血压及肠系膜三级动脉组织ACE、ACE2、Mas的m RNA及蛋白表达的影响
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摘要
目的观察天麻舒心方对自发性高血压大鼠(SHR)血压及肠系膜三级动脉组织血管紧张素转换酶(ACE)、ACE2及Mas的mRNA及蛋白表达的影响,探讨SHR阻力血管富营养重塑及天麻舒心方的干预机制。方法 80只SHR按照随机数字表法分为中药高、中、低剂量组,西药对照组,模型对照组,每组各16只,分别予天麻舒心浸膏液高剂量[11.592 g/(kg·d)]、中剂量[5.796 g/(kg·d)]、低剂量[2.898 g/(kg·d)]、氯沙坦钾混悬液、蒸馏水,15只Wistar大鼠作为正常对照。每2周测量1次鼠尾动脉血压。18周后处死动物,分离肠系膜三级动脉,采用Western blot和RT-PCR检测各组ACE、ACE2及Mas的蛋白和mRNA表达。结果给药2周后,各给药组血压均显著低于模型对照组(P <0.01)。相对于正常对照组,模型对照组ACE mRNA及蛋白表达显著增加(P <0.05或P <0.01),ACE2 mRNA及Mas m RNA含量及蛋白表达显著减少(P <0.05或P <0.01)。与模型对照组比较,中药高剂量组ACE mRNA表达降低(P <0.05),Mas mRNA表达增加(P <0.05),ACE2、Mas蛋白表达增加(P <0.01);中药中剂量组ACE mRNA和蛋白表达均降低(P <0.05),ACE2 mRNA表达增加(P <0.05),Mas蛋白表达增加(P <0.01);中药低剂量组ACE m RNA表达降低(P <0.05),Mas mRNA和蛋白表达增加(P <0.05或P <0.01)。结论天麻舒心方对SHR血压具有较好控制作用。ACE合成增多,ACE2及Mas合成减少可能是高血压阻力血管富营养重塑病理机制之一。平肝活血中药可逆转ACE、ACE2比例失衡,增加Mas表达,通过ACE2/Ang-(1-7)/Mas通路的干预,逆转RAS失衡,改善高血压阻力血管富营养重塑,减轻靶器官损害。
Objective To observe the effect of Tianma Shuxin Granules(TSG) to spontaneous hypertensive rats(SHRs)on the blood pressure(BP), as well as the mRNA and protein expression of angiotensin-converting enzyme(ACE),ACE2 and Mas in the third-order branches of mesenteric arteries, and investigate the possible mechanisms of SHRs′resistance vascular eutrophic remodeling and the intervention of TSG. Methods Eighty male SPF SHRs were divided into five groups with 16 rats in each group according to the random number table method: high dosage traditional Chinese medicine group [11.592 g/(kg·d) TSG], medium dosage traditional Chinese medicine group [5.796 g/(kg·d) TSG]and low dosage traditional Chinese medicine group [2.898 g/(kg·d) TSG], Western medicine control group and model control group were treated with TSG, Losartan Potassium Suspension and distilled water respectively. Fifteen Wistar rats were taken as normal control group. The BP of rat tail artery was measured fortnightly. After 18 weeks,rats in each group were killed and the mesenteric arteries were separated. The protein and m RNA expression of ACE, ACE2 and Mas were measured by Western blot and RT-PCR respectively. Results After 2 weeks of administration, the BP of the Western medicine control group, the high dosage traditional Chinese medicine group and the middle dosage traditional Chinese medicine group were significantly lower than that of the model control group(P < 0.01).Compared with the normal control group, the mRNA and protein expression of ACE in the model control group were increased significantly(P < 0.05 or P < 0.01), and the content and the protein expression of m RNA of ACE2 and Mas were decreased significantly(P < 0.05 or P < 0.01). Compared with the model control group, the mRNA expression of ACE in the high dosage traditional Chinese medicine group was decreased(P < 0.05), the m RNA expression of Mas was increased(P < 0.05), the protein expression of ACE2 and Mas were increased(P < 0.01). The m RNA and protein expression of ACE were decreased(P < 0.05), the mRNA expression of ACE2 and the protein expression of Mas were increased in the medium dosage traditional Chinese medicine group(P < 0.05 or P < 0.01). The mRNA expression of ACE was decreased(P < 0.05), the mRNA and protein expression of Mas were increased in the low dosage traditional Chinese medicine group(P < 0.05 or P < 0.01). Conclusion TSG has markedly effect in lowering SHRs′ BP. Increased synthesis of ACE, and decreased synthesis of ACE2 and Mas may be one of the pathological mechanisms of vascular nutrition-rich remodeling in hypertension resistance. TSG can reverse the imbalance of ACE and ACE2, increase the expression of Mas, it can reverse the imbalance of RAS by means of interfering the ACE2-Ang(1-7)-Mas pathways, it is beneficial to improve the vascular hypertension resistance eutrophic remodeling and reduce the target-organ damage.
Objective To observe the effect of Tianma Shuxin Granules(TSG) to spontaneous hypertensive rats(SHRs)on the blood pressure(BP), as well as the mRNA and protein expression of angiotensin-converting enzyme(ACE),ACE2 and Mas in the third-order branches of mesenteric arteries, and investigate the possible mechanisms of SHRs′resistance vascular eutrophic remodeling and the intervention of TSG. Methods Eighty male SPF SHRs were divided into five groups with 16 rats in each group according to the random number table method: high dosage traditional Chinese medicine group [11.592 g/(kg·d) TSG], medium dosage traditional Chinese medicine group [5.796 g/(kg·d) TSG]and low dosage traditional Chinese medicine group [2.898 g/(kg·d) TSG], Western medicine control group and model control group were treated with TSG, Losartan Potassium Suspension and distilled water respectively. Fifteen Wistar rats were taken as normal control group. The BP of rat tail artery was measured fortnightly. After 18 weeks,rats in each group were killed and the mesenteric arteries were separated. The protein and m RNA expression of ACE, ACE2 and Mas were measured by Western blot and RT-PCR respectively. Results After 2 weeks of administration, the BP of the Western medicine control group, the high dosage traditional Chinese medicine group and the middle dosage traditional Chinese medicine group were significantly lower than that of the model control group(P < 0.01).Compared with the normal control group, the mRNA and protein expression of ACE in the model control group were increased significantly(P < 0.05 or P < 0.01), and the content and the protein expression of m RNA of ACE2 and Mas were decreased significantly(P < 0.05 or P < 0.01). Compared with the model control group, the mRNA expression of ACE in the high dosage traditional Chinese medicine group was decreased(P < 0.05), the m RNA expression of Mas was increased(P < 0.05), the protein expression of ACE2 and Mas were increased(P < 0.01). The m RNA and protein expression of ACE were decreased(P < 0.05), the mRNA expression of ACE2 and the protein expression of Mas were increased in the medium dosage traditional Chinese medicine group(P < 0.05 or P < 0.01). The mRNA expression of ACE was decreased(P < 0.05), the mRNA and protein expression of Mas were increased in the low dosage traditional Chinese medicine group(P < 0.05 or P < 0.01). Conclusion TSG has markedly effect in lowering SHRs′ BP. Increased synthesis of ACE, and decreased synthesis of ACE2 and Mas may be one of the pathological mechanisms of vascular nutrition-rich remodeling in hypertension resistance. TSG can reverse the imbalance of ACE and ACE2, increase the expression of Mas, it can reverse the imbalance of RAS by means of interfering the ACE2-Ang(1-7)-Mas pathways, it is beneficial to improve the vascular hypertension resistance eutrophic remodeling and reduce the target-organ damage.
引文
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[3]陶蓉.肾素-血管紧张素系统抑制剂治疗高血压的研究进展[J].上海医药,2013,34(19):10-13.
[4]Forrester SJ,Booz GW,Sigmund CD,et al.AngiotensinⅡSignal Transduction:An Update on Mechanisms of Physiology and Pathophysiology[J].Physiol Rev,2018,98(3):1627-1738.
[5]Mckinney CA,Fattah C,Loughrey CM,et al.Angiotensin-(1-7)and angiotensin-(1-9):function in cardiac and vascular remodelling[J].Clin Sci,2014,126(12):815-827.
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[7]潘立敏,王洋,刘坤,等.天麻舒心方对SHR左心室超微结构及胶原的影响[J].中西医结合心脑血管病杂志,2018,16(5):554-557.
[8]王洋,刘坤,尹倚艰,等.天麻舒心方对自发性高血压大鼠阻力血管富营养重塑的干预效果[J].北京中医药,2017,36(4):321-325.
[9]郝潇,李树仁.血管紧张素-(1-9)心脏保护性作用研究进展[J].中国循环杂志,2015,30(12):1247-1249.
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[11]Zhang F,Hu YH,Xu QB,et al.Different effects of angiotensinⅡand angiotensin-(1-7)on vascular smooth muscle cell proliferation and migration[J].PLoS One,2010,5(8):e12323.
[12]Zhang K,Meng X,Li D,et al.Angiotensin(1-7)attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade[J].Kidney Int,2015,87(2):359-369.
[13]柏松.新型肾素-血管紧张素系统治疗高血压的研究进展[J].中国当代医药,2016,23(16):19-21.
[14]Wang Y,Tikellis C,Thomas MC,et al.Angiotensin converting enzyme 2 and atherosclerosis[J].Atherosclerosis,2013,226:3-8.
[15]Iwai M,Nakaoka H,Senba I,et al.Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensinⅡType 1 receptor blockade on vascular remodeling[J].Hypertension,2012,60(1):137-144.
[16]SeváPess觝a B,van der Lubbe N,Verdonk K,et al.Key developments in renin-angiotensin-aldosterone system inhibition[J].Nat Rev Nephrol,2013,9(1):26-36.
[17]喻江标,吴永港,张银妆,等.ACE2-Ang(1-7)-Mas受体轴在高血压射血分数保留心力衰竭中的作用[J].中南大学学报:医学版,2018,43(7):738-746.
[18]张晓翠,侯兆玉,张红利,等.血管紧张素1-7通过Mas受体减轻血管紧张素Ⅱ所致人肾小球内皮细胞损伤[J].中国病理生理杂志,2018,34(5):893-898.
[19]Ohshima K,Mogi M,Nakaoka H,et al.Possible role of angiotensin-converting enzyme 2 and activation of angiotensinⅡtype 2 receptor by angiotensin-(1-7)in improvement of vascular remodeling by angiotensinⅡtype 1 receptor blockade[J].Hypertension,2014,63(3):e53-e59.
[20]Castro MM,Rizzi E,Rodrigues GJ,et al.Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension[J].Free Radical Bio Med,2009,46(9):1298-1307.
[2]康玉明,李宏宝,齐杰,等.高血压中枢发病机制的研究进展[J].西安交通大学学报:医学版,2017,38(1):1-6.
[3]陶蓉.肾素-血管紧张素系统抑制剂治疗高血压的研究进展[J].上海医药,2013,34(19):10-13.
[4]Forrester SJ,Booz GW,Sigmund CD,et al.AngiotensinⅡSignal Transduction:An Update on Mechanisms of Physiology and Pathophysiology[J].Physiol Rev,2018,98(3):1627-1738.
[5]Mckinney CA,Fattah C,Loughrey CM,et al.Angiotensin-(1-7)and angiotensin-(1-9):function in cardiac and vascular remodelling[J].Clin Sci,2014,126(12):815-827.
[6]Xu P,Sriramula S,Lazartigues E.ACE2/ANG-(1-7)/Mas pathway in the brain:the axis of good[J].Am J PhysiolReg I,2011,300(4):R804-R817.
[7]潘立敏,王洋,刘坤,等.天麻舒心方对SHR左心室超微结构及胶原的影响[J].中西医结合心脑血管病杂志,2018,16(5):554-557.
[8]王洋,刘坤,尹倚艰,等.天麻舒心方对自发性高血压大鼠阻力血管富营养重塑的干预效果[J].北京中医药,2017,36(4):321-325.
[9]郝潇,李树仁.血管紧张素-(1-9)心脏保护性作用研究进展[J].中国循环杂志,2015,30(12):1247-1249.
[10]吴剑,邹云增.ACE/AngⅡ/AT1轴与ACE2/Ang(1-7)/Mas轴的平衡失调在心血管病中的作用[J].中国医学前沿杂志:电子版,2013,5(6):43-47.
[11]Zhang F,Hu YH,Xu QB,et al.Different effects of angiotensinⅡand angiotensin-(1-7)on vascular smooth muscle cell proliferation and migration[J].PLoS One,2010,5(8):e12323.
[12]Zhang K,Meng X,Li D,et al.Angiotensin(1-7)attenuates the progression of streptozotocin-induced diabetic renal injury better than angiotensin receptor blockade[J].Kidney Int,2015,87(2):359-369.
[13]柏松.新型肾素-血管紧张素系统治疗高血压的研究进展[J].中国当代医药,2016,23(16):19-21.
[14]Wang Y,Tikellis C,Thomas MC,et al.Angiotensin converting enzyme 2 and atherosclerosis[J].Atherosclerosis,2013,226:3-8.
[15]Iwai M,Nakaoka H,Senba I,et al.Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensinⅡType 1 receptor blockade on vascular remodeling[J].Hypertension,2012,60(1):137-144.
[16]SeváPess觝a B,van der Lubbe N,Verdonk K,et al.Key developments in renin-angiotensin-aldosterone system inhibition[J].Nat Rev Nephrol,2013,9(1):26-36.
[17]喻江标,吴永港,张银妆,等.ACE2-Ang(1-7)-Mas受体轴在高血压射血分数保留心力衰竭中的作用[J].中南大学学报:医学版,2018,43(7):738-746.
[18]张晓翠,侯兆玉,张红利,等.血管紧张素1-7通过Mas受体减轻血管紧张素Ⅱ所致人肾小球内皮细胞损伤[J].中国病理生理杂志,2018,34(5):893-898.
[19]Ohshima K,Mogi M,Nakaoka H,et al.Possible role of angiotensin-converting enzyme 2 and activation of angiotensinⅡtype 2 receptor by angiotensin-(1-7)in improvement of vascular remodeling by angiotensinⅡtype 1 receptor blockade[J].Hypertension,2014,63(3):e53-e59.
[20]Castro MM,Rizzi E,Rodrigues GJ,et al.Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension[J].Free Radical Bio Med,2009,46(9):1298-1307.
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