姜黄素对慢性心力衰竭大鼠肾素-血管紧张素-醛固酮系统和心功能的改善作用
|
摘要
目的:探讨姜黄素对慢性心力衰竭大鼠肾素(Renin)-血管紧张素Ⅱ(AngⅡ)-醛固酮(ALD)系统(RAAS)的调节作用,阐明其治疗机制。方法:选取雄性SD大鼠50只,随机分为假手术组,模型组,低、中和高剂量姜黄素组,每组10只。假手术组大鼠仅打开腹腔暴露左冠状动脉前降支但不做结扎,常规喂养,其余各组大鼠在剑突下腹部正中将腹腔打开,在左冠状动脉前降支结扎,建立大鼠慢性心力衰竭模型。低、中和高剂量姜黄素组大鼠分别灌胃给予20、40和80mg·kg-1姜黄素,假手术组和模型组以等量生理盐水代替,连续给药30d。利用超声心动图仪测量大鼠心功能;腹主动脉取血,ELISA检测各组大鼠血清中Renin、AngⅡ和ALD水平;RT-PCR法检测各组大鼠心肌组织中血管紧张素受体1型(AT1R)和血管紧张素转化酶(ACE)mRNA表达水平;Western blotting法检测各组大鼠心肌组织中ACE和AT1R蛋白表达水平。结果:与模型组比较,低、中和高剂量姜黄素组大鼠左心室收缩末期内径(LVESD)和左室舒张末期内径(LVEDD)明显降低(P<0.05),而左室射血分数(LVEF)明显升高(P<0.05);与模型组比较,低、中和高剂量姜黄素组大鼠血清中Renin、AngⅡ和ALD水平明显降低(P<0.05);与模型组比较,低、中和高剂量姜黄素组大鼠心肌组织中ACE和AT1RmRNA和蛋白表达水平明显降低(P<0.05);结论:姜黄素对慢性心力衰竭大鼠RAAS系统具有剂量依赖性抑制作用,并能改善慢性心力衰竭大鼠的心功能。
Objective:To investigate the regulatory effects of curcumin on Renin-angiotensinⅡ(AngⅡ)-aldosterone(ALD)system(RAAS)in the rats with chronic heart failure,and to elucidate its therapeutic mechanism.Methods:Fifty male SD rats were selected and randomly divided into sham operation group,model group,low dose of curcumin group,middle dose of crucumin group and high dose curcumin of group(n=10).In sham operation group,the left ventricles of the rats were opened only to expose the left anterior descending coronary artery without ligation and conventional feeding.The abdomen of the rats in other groups were opened in the xiphoid abdomen and the left anterior descending coronary arteries were ligated to establish the rat models with chronic heart failure.The rats in low,middle,and high doses of curcumin groups were intragastrically adminstrated with 20,40,and 80 mg·kg-1 curcumin,and the rats in sham operation group and model group were administrated with normal saline at the same volume;continuous administration for 30 d.The heart function of the rats was measured by echocardiography.The blood was taken from the abdominal aorta.ELISA was used to detect the levels of serum Renin,AngⅡ and ALD of the rats in various groups.The expression levels of angiotensin type 1 receptor(AT1 R)and agniotensin-converting enzyme(ACE)mRNA in myocardium tissue of the rats in various groups were detected by RT-PCR method.Western blotting method was used to detect the expression levels of ACE and AT1 Rproteins in myocardium tissue of the rats in various groups.Results:Compared with model group,the left ventricular end systolic diameter(LVESD)and left ventricular end diastolic diameter(LVEDD)in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05),while the left ventricular ejection fraction(LVEF)were significantly increased(P<0.05).Compared with model group,the levels of Renin,AngⅡand ALD in the serum of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05).Compared with model group,the expression levels of ACE and AT1 R mRNA in the myocardium tissue of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05);compared with model group,the expression levels of ACE and AT1 Rproteins in the myocardium tissue of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05).Conclusion:Curcumin has a dose-dependent inhibition for the RAAS in the chronic heart failue rats and can improve the cardiac function of the chronic heart failure rats.
Objective:To investigate the regulatory effects of curcumin on Renin-angiotensinⅡ(AngⅡ)-aldosterone(ALD)system(RAAS)in the rats with chronic heart failure,and to elucidate its therapeutic mechanism.Methods:Fifty male SD rats were selected and randomly divided into sham operation group,model group,low dose of curcumin group,middle dose of crucumin group and high dose curcumin of group(n=10).In sham operation group,the left ventricles of the rats were opened only to expose the left anterior descending coronary artery without ligation and conventional feeding.The abdomen of the rats in other groups were opened in the xiphoid abdomen and the left anterior descending coronary arteries were ligated to establish the rat models with chronic heart failure.The rats in low,middle,and high doses of curcumin groups were intragastrically adminstrated with 20,40,and 80 mg·kg-1 curcumin,and the rats in sham operation group and model group were administrated with normal saline at the same volume;continuous administration for 30 d.The heart function of the rats was measured by echocardiography.The blood was taken from the abdominal aorta.ELISA was used to detect the levels of serum Renin,AngⅡ and ALD of the rats in various groups.The expression levels of angiotensin type 1 receptor(AT1 R)and agniotensin-converting enzyme(ACE)mRNA in myocardium tissue of the rats in various groups were detected by RT-PCR method.Western blotting method was used to detect the expression levels of ACE and AT1 Rproteins in myocardium tissue of the rats in various groups.Results:Compared with model group,the left ventricular end systolic diameter(LVESD)and left ventricular end diastolic diameter(LVEDD)in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05),while the left ventricular ejection fraction(LVEF)were significantly increased(P<0.05).Compared with model group,the levels of Renin,AngⅡand ALD in the serum of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05).Compared with model group,the expression levels of ACE and AT1 R mRNA in the myocardium tissue of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05);compared with model group,the expression levels of ACE and AT1 Rproteins in the myocardium tissue of the rats in low,middle,and high doses of curcumin groups were significantly decreased(P<0.05).Conclusion:Curcumin has a dose-dependent inhibition for the RAAS in the chronic heart failue rats and can improve the cardiac function of the chronic heart failure rats.
引文
[1]邱伯雍,王永霞.慢性心力衰竭流行病学及防治研究进展[J].中华实用诊断与治疗杂志,2017,31(6):619-621.
[2]黄峻.中国心力衰竭流行病学特点和防治策略[J].中华心脏与心律电子杂志,2015,3(2):81-82.
[3]叶青,程晓昱.中医药治疗慢性心力衰竭研究概况[J].中医药临床杂志,2016,28(4):464-467.
[4]周亚滨,邬慧美,孙静,等.慢性心力衰竭中医治疗进展[J].辽宁中医药大学学报,2016,18(1):8-10.
[5]SAYER G,BHAT G.The renin-angiotensin-aldosterone system and heart failure[J].Cardiol Clin,2014,32(1):21-32,vii.
[6]TAMARGO J,CABALLERO R,DELPN E.New therapeutic approaches for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors[J].Cardiovasc Drugs Ther,2018,32(1):99-119.
[7]KHAN M S,FONAROW G C,KHAN H,et al.Reninangiotensin blockade in heart failure with preserved ejection fraction:a systematic review and meta-analysis[J].ESCHeart Fail,2017,4(4):402-408.
[8]ZHANG C L,LI B Q,ZHANG X,et al.Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients’PBMCs:potential role for STAT-3and NF-kappaBsignaling[J].J Invest Dermatol,2010,130(8):2110-2119.
[9]MARCU M G,JUNG Y J,LEE S,et al.Curcumin is an inhibitor of p300histone acetylatransferase[J].Med Chem,2006,2(2):169-174.
[10]文建霞,王建,张璐,等.大鼠慢性心力衰竭模型研究现状[J].中国医院用药评价与分析,2017,17(9):1157-1159.
[11]宋永周,童九辉,马维,等.姜黄素对软骨细胞氧化应激损伤的保护作用[J].河北医药,2016,38(23):3525-3528.
[12]王晓静.MAPK信号转导通路在姜黄素预处理大鼠脑缺血再灌注损伤中的表达变化[D].蚌埠:蚌埠医学院,2010.
[13]ALLIDA S M,INGLIS S C,DAVIDSON P M,et al.Asurvey of views and opinions of health professionals managing thirst in chronic heart failure[J].Contemp Nurse,2016,52(2/3):244-252.
[14]HNIN E,MEILLE C,BARBOLOSI D,et al.Revisiting dosing regimen using PK/PD modeling:the MODEL1phaseⅠ/Ⅱtrial of docetaxel plus epirubicin in metastatic breast cancer patients[J].Breast Cancer Res Treat,2016,156(2):331-341.
[15]TOI M,SAEKI T,IWATA H,et al.A multicenter phaseⅡstudy of TSU-68,an oral multiple tyrosine kinase inhibitor,in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance[J].Breast Cancer,2014,21(1):20-27.
[16]UEDA S,KAWAKAMI H,NISHINA S,et al.Phase I trial of 5-FU,docetaxel,and nedaplatin(UDON)combination therapy for recurrent or metastatic esophageal cancer[J].Cancer Chemother Pharmacol,2015,76(2):279-285.
[17]LUKE J J,LORUSSO P,SHAPIRO G I,et al.ASP9853,an inhibitor of inducible nitric oxide synthase dimerization,in combination with docetaxel:preclinical investigation and a PhaseⅠstudy in advanced solid tumors[J].Cancer Chemother Pharmacol,2016,77(3):549-558.
[18]LORUSSO P M,INFANTE J R,KIM K B,et al.A phaseⅠdose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors[J].BMC Cancer,2017,17(1):173.
[19]PITT B,BAKRIS G L,BUSHINSKY D A,et al.Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors[J].Eur J Heart Fail,2015,17(10):1057-1065.
[20]WEIR M R,BAKRIS G L,BUSHINSKY D A,et al.Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors[J].N Engl J Med,2015,372(3):211-221.
[21]WEIR M R,BAKRIS G L,GROSS C,et al.Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors[J].Kidney Int,2016,90(3):696-704.
[22]PERGOLA P E,SPIEGEL D M,WARREN S,et al.Patiromer lowers serum potassium when taken without food:comparison to dosing with food from an open-label,randomized,parallel group hyperkalemia study[J].Am JNephrol,2017,46(4):323-332.
[2]黄峻.中国心力衰竭流行病学特点和防治策略[J].中华心脏与心律电子杂志,2015,3(2):81-82.
[3]叶青,程晓昱.中医药治疗慢性心力衰竭研究概况[J].中医药临床杂志,2016,28(4):464-467.
[4]周亚滨,邬慧美,孙静,等.慢性心力衰竭中医治疗进展[J].辽宁中医药大学学报,2016,18(1):8-10.
[5]SAYER G,BHAT G.The renin-angiotensin-aldosterone system and heart failure[J].Cardiol Clin,2014,32(1):21-32,vii.
[6]TAMARGO J,CABALLERO R,DELPN E.New therapeutic approaches for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors[J].Cardiovasc Drugs Ther,2018,32(1):99-119.
[7]KHAN M S,FONAROW G C,KHAN H,et al.Reninangiotensin blockade in heart failure with preserved ejection fraction:a systematic review and meta-analysis[J].ESCHeart Fail,2017,4(4):402-408.
[8]ZHANG C L,LI B Q,ZHANG X,et al.Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients’PBMCs:potential role for STAT-3and NF-kappaBsignaling[J].J Invest Dermatol,2010,130(8):2110-2119.
[9]MARCU M G,JUNG Y J,LEE S,et al.Curcumin is an inhibitor of p300histone acetylatransferase[J].Med Chem,2006,2(2):169-174.
[10]文建霞,王建,张璐,等.大鼠慢性心力衰竭模型研究现状[J].中国医院用药评价与分析,2017,17(9):1157-1159.
[11]宋永周,童九辉,马维,等.姜黄素对软骨细胞氧化应激损伤的保护作用[J].河北医药,2016,38(23):3525-3528.
[12]王晓静.MAPK信号转导通路在姜黄素预处理大鼠脑缺血再灌注损伤中的表达变化[D].蚌埠:蚌埠医学院,2010.
[13]ALLIDA S M,INGLIS S C,DAVIDSON P M,et al.Asurvey of views and opinions of health professionals managing thirst in chronic heart failure[J].Contemp Nurse,2016,52(2/3):244-252.
[14]HNIN E,MEILLE C,BARBOLOSI D,et al.Revisiting dosing regimen using PK/PD modeling:the MODEL1phaseⅠ/Ⅱtrial of docetaxel plus epirubicin in metastatic breast cancer patients[J].Breast Cancer Res Treat,2016,156(2):331-341.
[15]TOI M,SAEKI T,IWATA H,et al.A multicenter phaseⅡstudy of TSU-68,an oral multiple tyrosine kinase inhibitor,in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance[J].Breast Cancer,2014,21(1):20-27.
[16]UEDA S,KAWAKAMI H,NISHINA S,et al.Phase I trial of 5-FU,docetaxel,and nedaplatin(UDON)combination therapy for recurrent or metastatic esophageal cancer[J].Cancer Chemother Pharmacol,2015,76(2):279-285.
[17]LUKE J J,LORUSSO P,SHAPIRO G I,et al.ASP9853,an inhibitor of inducible nitric oxide synthase dimerization,in combination with docetaxel:preclinical investigation and a PhaseⅠstudy in advanced solid tumors[J].Cancer Chemother Pharmacol,2016,77(3):549-558.
[18]LORUSSO P M,INFANTE J R,KIM K B,et al.A phaseⅠdose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors[J].BMC Cancer,2017,17(1):173.
[19]PITT B,BAKRIS G L,BUSHINSKY D A,et al.Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors[J].Eur J Heart Fail,2015,17(10):1057-1065.
[20]WEIR M R,BAKRIS G L,BUSHINSKY D A,et al.Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors[J].N Engl J Med,2015,372(3):211-221.
[21]WEIR M R,BAKRIS G L,GROSS C,et al.Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors[J].Kidney Int,2016,90(3):696-704.
[22]PERGOLA P E,SPIEGEL D M,WARREN S,et al.Patiromer lowers serum potassium when taken without food:comparison to dosing with food from an open-label,randomized,parallel group hyperkalemia study[J].Am JNephrol,2017,46(4):323-332.