Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and c...Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.展开更多
Background Transforming growth factor （TGF） β1-Smads signal plays an important role in cardiac remodeling following myocardial infarction （MI）. In addition, both angiotensin converting enzyme inhibitor （ACEI） a...Background Transforming growth factor （TGF） β1-Smads signal plays an important role in cardiac remodeling following myocardial infarction （MI）. In addition, both angiotensin converting enzyme inhibitor （ACEI） and angiotensin Ⅱ type Ⅰ receptor blocker （ARB） can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect. Methods MI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks： placebo group, ACEI group （benazepril 10 mg · kg^-1· d^-1）, ARB group （irbesartan 50mg · kg^-1· d^-1）, ACEI＋ARB group （benazepril 10 mg · kg^-1· d^-1＋irbesartan 50 mg · kg^-1· d^-1） and control group （sham-operated rats）. After 8 weeks, we examined the following indexes： the ratio of ventricular weight to body weight （VW/BW）, left ventricular end diastolic dimension （LVDd）, ejection fraction （EF）, fractional shortening （FS）, ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFβ1, Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot. Results VW/BW significantly increased in the placebo groups compared with that in the control group （P〈0.01）. This increase was limited in ACEI, ARB, and combined groups （P〈0.01 compared with placebo group）. There was no significant difference among the three actively treated groups. Collagen was increased in placebo group （5.68±0.5）% compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment attenuated this increase of collagen [（4.3 ± 0.5）%, （3.5 ± 0.5）%, （3.2± 0.4）%] in comparison with that in placebo group （P〈0.01 respectively）. Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group （P〈0.01 respectively）. ACEI, ARB and combined treatment ameliorated these indexes （P〈0.01 compared with placebo group）. The mRNA expression of TGFβ1, Smad 2, and Smad 3 （0.700±0.045, 0.959±0.037 and 0.850±0.051） increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF β1 and Smad mRNA expression than ACEI treatment （P〈0.01）. The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective than ACEI alone （P〈0.01）.Conclusions TGFβ1-Smads signal activation is correlated With ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.展开更多
Background Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density （BMD） in older people, especially male subjects, which suggested that ...Background Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density （BMD） in older people, especially male subjects, which suggested that angiotensin II may have a detrimental effect on bone. Therefore, blocking its effect may have a beneficial effect on bone health. Methods Six-month-old male spontaneously hypertensive rats （SHR） and normotensive Wistar Kyoto rats （WKY） were used. Animals of each model were randomly assigned to the following four groups： Group 1, SHAM operated＋vehicle; Group 2, orchidectomy （ORX）＋vehicle; Group 3, ORX＋low-dose Iosartan （10 mg.kgl.dl）; and Group 4, ORX＋high-dose Iosartan （25 mg-kg-l.d-1）. Blood pressure was recorded weekly. SHAM and ORX operations were performed, followed by daily Iosartan and vehicle treatment from day 4 after operation for 16 weeks. Serum and 24-hour urine samples were collected for measurement of bone turnover markers before euthanasia and then the left femur was collected for measurements of BMD and microarchitecture before mechanical test. Results Urine deoxypyridinoline/urine creatinine （DPD/Cr） ratio was significantly higher in SHR than in WKY. BMD and microarchitecture parameters also showed bone deterioration in SHR. After ORX, serum osteocalcin concentration decreased and urine DPD/Cr ratio increased significantly accompanied by a significant decrease in cortical and trabecular BMD and cortical bone thickness in both WKY and SHR. High-dose Iosartan significantly increased DPD in urine in both SHR and WKY. Apart from marginal favorable changes in bone architecture in WKY treated with high-dose Iosartan, Iosartan did not show significant effect on BMD, bone area, bone microarchitecture, and mechanical properties in both SHR and WKY. Conclusion Angiotensin II type I receptor blocker Iosartan was not able to demonstrate significant effect on ORX-induced bone deterioration in both hypertensive and normotensive rats.展开更多
目的:观察激活G蛋白偶联雌激素受体1(GPER1)对血管紧张素Ⅱ(AngⅡ)诱导心肌细胞肥大的影响,并探讨其可能的机制。方法:2~3日龄乳鼠心肌细胞体外原代培养。利用串联质谱标签(TMT)蛋白质谱技术检测蛋白表达差异,并作相关生物信息学分析,...目的:观察激活G蛋白偶联雌激素受体1(GPER1)对血管紧张素Ⅱ(AngⅡ)诱导心肌细胞肥大的影响,并探讨其可能的机制。方法:2~3日龄乳鼠心肌细胞体外原代培养。利用串联质谱标签(TMT)蛋白质谱技术检测蛋白表达差异,并作相关生物信息学分析,筛查其可能的调节机制。机制研究分6组,空白对照组、AngⅡ组、AngⅡ+GPER1激活剂(G1)组、AngⅡ+G1+GPER1抑制剂(G15)组、AngⅡ+G1+细胞外调节蛋白激酶(ERK)抑制剂(U0126)组和AngⅡ+G1+丝氨酸/苏氨酸激酶(AKT)抑制剂(MK2206)组,各组n=3。检测各组心肌细胞GPER1的表达,心房钠尿肽(ANP)和B型利钠肽(BNP)的m RNA水平,ERK、AKT蛋白的表达及其相互作用,以及对自噬相关蛋白胞浆型自噬标记轻链3(LC3II)和膜型自噬标记轻链3(LC3I)的调控。流式细胞技术检测GPER1对细胞凋亡的影响。结果:AngⅡ诱导心肌细胞肥大呈浓度依赖性,ANP和BNP m RNA水平梯度升高(P<0.05)。细胞免疫荧光染色显示,心肌细胞上存在GPER1蛋白表达。荧光定量逆转录聚合酶链式反应(q RT-PCR)结果显示,激活剂G1激活GPER1,并以浓度依赖方式抑制心肌细胞ANP和BNP m RNA水平(P<0.05);在AngⅡ+G1+G15组,心肌细胞ANP和BNP m RNA水平重新升高(P<0.05)。蛋白免疫印迹法(Western-blot)结果显示,与空白对照组或AngⅡ组相比,AngⅡ+G1组p-ERK、p-AKT蛋白表达增强(P<0.05);与AngⅡ+G1组相比,AngⅡ+G1+G15组p-ERK和p-AKT蛋白表达降低(P<0.05),AngⅡ+G1+MK2206组p-ERK、p-AKT蛋白表达水平和ANP、BNP m RNA水平降低(P<0.05);AngⅡ+G1+U0126组对G1诱导的p-AKT蛋白的表达无影响。流式细胞技术显示,AngⅡ+G1组与AngⅡ组心肌细胞凋亡水平无差异(P>0.05)。AngⅡ组较空白对照组LC3II/LC3I比值增大,其自噬水平显著升高(P<0.01)。而AngⅡ+G1组较AngⅡ组LC3II/LC3I比值降低,其心肌细胞自噬水平降低(P<0.01)。结论:GPER1的激活抑制心肌细胞肥大,其作用机制可能与AKT和ERK信号通路以及细胞自噬相关。展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(No.81100814,No.91539202,No.81230071 and No.81571630)the Shanghai Municipal Commission of Health and Farmily Planning(No.201540222 and No.2017YQ076).
文摘Vascular remodeling is an adaptive response to various stimuli,including mechanical forces,inflammatory cy tokines and hormones.In the present study,we investigated the role of angiotensinII type 1 receptor(ATIR)and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction(TAC)rat model.TAC was induced on ten week-old male Sprague Dawley rats and these models were treated with ATIR blocker olmesartan(1 mg/kg/day)or/and calcium channel blocker(CCB)amlodipine(0.5 mgkgday)for 14 days.After the treatment,the right common carotid artery proximal to the band(RCCA-B)was collected for further assay.Results showed that olmesartan,but not amlodipine,significantly prevented TAC-induced adventitial hyperplasia.Similarly,olmesartan,but not amlodipine,significantly prevented vascular inflammation,as indicated by increased tumor necrosis factor a(TNF-a)and increased p65 phosphorylation,an indicator of nuclear factor K-light-chain-enhancer of activated B cells(NFkB)activation in RCCA-B.In contrast,both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase(eNOS)and improved endothelium-dependent vasodilation,whereas combination of olmesartan and amlodipine showed no further synergistic protective effects.These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload,whereas ATIR and subsequent calcium channel were involved in endothelial dysfunction.
基金The project was supported by a grant from the Natural Science Foundation of Heilongjiang Province (No. D0239) and the Post Doctor Foundation of Heilongjiang Province.
文摘Background Transforming growth factor （TGF） β1-Smads signal plays an important role in cardiac remodeling following myocardial infarction （MI）. In addition, both angiotensin converting enzyme inhibitor （ACEI） and angiotensin Ⅱ type Ⅰ receptor blocker （ARB） can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect. Methods MI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks： placebo group, ACEI group （benazepril 10 mg · kg^-1· d^-1）, ARB group （irbesartan 50mg · kg^-1· d^-1）, ACEI＋ARB group （benazepril 10 mg · kg^-1· d^-1＋irbesartan 50 mg · kg^-1· d^-1） and control group （sham-operated rats）. After 8 weeks, we examined the following indexes： the ratio of ventricular weight to body weight （VW/BW）, left ventricular end diastolic dimension （LVDd）, ejection fraction （EF）, fractional shortening （FS）, ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFβ1, Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot. Results VW/BW significantly increased in the placebo groups compared with that in the control group （P〈0.01）. This increase was limited in ACEI, ARB, and combined groups （P〈0.01 compared with placebo group）. There was no significant difference among the three actively treated groups. Collagen was increased in placebo group （5.68±0.5）% compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment attenuated this increase of collagen [（4.3 ± 0.5）%, （3.5 ± 0.5）%, （3.2± 0.4）%] in comparison with that in placebo group （P〈0.01 respectively）. Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group （P〈0.01 respectively）. ACEI, ARB and combined treatment ameliorated these indexes （P〈0.01 compared with placebo group）. The mRNA expression of TGFβ1, Smad 2, and Smad 3 （0.700±0.045, 0.959±0.037 and 0.850±0.051） increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF β1 and Smad mRNA expression than ACEI treatment （P〈0.01）. The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective than ACEI alone （P〈0.01）.Conclusions TGFβ1-Smads signal activation is correlated With ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.
基金This study was partially supported by a direct research grant from The Chinese University of Hong Kong （No. 2006.2.017）, the Natural Science Foundation of Jiangsu Province, China （No. BK2010285）, and the Collegiate Natural Science Fund of Jiangsu Province, China （No. 10KJB320015）.
文摘Background Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density （BMD） in older people, especially male subjects, which suggested that angiotensin II may have a detrimental effect on bone. Therefore, blocking its effect may have a beneficial effect on bone health. Methods Six-month-old male spontaneously hypertensive rats （SHR） and normotensive Wistar Kyoto rats （WKY） were used. Animals of each model were randomly assigned to the following four groups： Group 1, SHAM operated＋vehicle; Group 2, orchidectomy （ORX）＋vehicle; Group 3, ORX＋low-dose Iosartan （10 mg.kgl.dl）; and Group 4, ORX＋high-dose Iosartan （25 mg-kg-l.d-1）. Blood pressure was recorded weekly. SHAM and ORX operations were performed, followed by daily Iosartan and vehicle treatment from day 4 after operation for 16 weeks. Serum and 24-hour urine samples were collected for measurement of bone turnover markers before euthanasia and then the left femur was collected for measurements of BMD and microarchitecture before mechanical test. Results Urine deoxypyridinoline/urine creatinine （DPD/Cr） ratio was significantly higher in SHR than in WKY. BMD and microarchitecture parameters also showed bone deterioration in SHR. After ORX, serum osteocalcin concentration decreased and urine DPD/Cr ratio increased significantly accompanied by a significant decrease in cortical and trabecular BMD and cortical bone thickness in both WKY and SHR. High-dose Iosartan significantly increased DPD in urine in both SHR and WKY. Apart from marginal favorable changes in bone architecture in WKY treated with high-dose Iosartan, Iosartan did not show significant effect on BMD, bone area, bone microarchitecture, and mechanical properties in both SHR and WKY. Conclusion Angiotensin II type I receptor blocker Iosartan was not able to demonstrate significant effect on ORX-induced bone deterioration in both hypertensive and normotensive rats.
文摘目的:观察激活G蛋白偶联雌激素受体1(GPER1)对血管紧张素Ⅱ(AngⅡ)诱导心肌细胞肥大的影响,并探讨其可能的机制。方法:2~3日龄乳鼠心肌细胞体外原代培养。利用串联质谱标签(TMT)蛋白质谱技术检测蛋白表达差异,并作相关生物信息学分析,筛查其可能的调节机制。机制研究分6组,空白对照组、AngⅡ组、AngⅡ+GPER1激活剂(G1)组、AngⅡ+G1+GPER1抑制剂(G15)组、AngⅡ+G1+细胞外调节蛋白激酶(ERK)抑制剂(U0126)组和AngⅡ+G1+丝氨酸/苏氨酸激酶(AKT)抑制剂(MK2206)组,各组n=3。检测各组心肌细胞GPER1的表达,心房钠尿肽(ANP)和B型利钠肽(BNP)的m RNA水平,ERK、AKT蛋白的表达及其相互作用,以及对自噬相关蛋白胞浆型自噬标记轻链3(LC3II)和膜型自噬标记轻链3(LC3I)的调控。流式细胞技术检测GPER1对细胞凋亡的影响。结果:AngⅡ诱导心肌细胞肥大呈浓度依赖性,ANP和BNP m RNA水平梯度升高(P<0.05)。细胞免疫荧光染色显示,心肌细胞上存在GPER1蛋白表达。荧光定量逆转录聚合酶链式反应(q RT-PCR)结果显示,激活剂G1激活GPER1,并以浓度依赖方式抑制心肌细胞ANP和BNP m RNA水平(P<0.05);在AngⅡ+G1+G15组,心肌细胞ANP和BNP m RNA水平重新升高(P<0.05)。蛋白免疫印迹法(Western-blot)结果显示,与空白对照组或AngⅡ组相比,AngⅡ+G1组p-ERK、p-AKT蛋白表达增强(P<0.05);与AngⅡ+G1组相比,AngⅡ+G1+G15组p-ERK和p-AKT蛋白表达降低(P<0.05),AngⅡ+G1+MK2206组p-ERK、p-AKT蛋白表达水平和ANP、BNP m RNA水平降低(P<0.05);AngⅡ+G1+U0126组对G1诱导的p-AKT蛋白的表达无影响。流式细胞技术显示,AngⅡ+G1组与AngⅡ组心肌细胞凋亡水平无差异(P>0.05)。AngⅡ组较空白对照组LC3II/LC3I比值增大,其自噬水平显著升高(P<0.01)。而AngⅡ+G1组较AngⅡ组LC3II/LC3I比值降低,其心肌细胞自噬水平降低(P<0.01)。结论:GPER1的激活抑制心肌细胞肥大,其作用机制可能与AKT和ERK信号通路以及细胞自噬相关。
