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1.
AIM and METHODS:To investigate the role of angiotensin Ⅱ recepters(ATRs) in overload pressure-induced left ventricular hypertrophy. The rat abdominal aortic constraction model was adopted. At 10th week after operating, angiotensin Ⅱ in myocardium was measured by radioimmunoassay,tissue ATRs and its subtype were analysed by radioligand binding assay. RESULTS: The AngⅡ content in the operated group was significantly higher than that of the control group, LVMI was positively correlated with AngⅡ(r=0.8066,P＜0.01).The maximal binding capacity of ATRs in the operated group was significantly higher than that of the control group(P＜0.01). However,the equilibrium dissociation constant(kd) and ratio of AT1R to AT2R in these two groups had no significantly different. Left ventricular hypertrophy was significantly reduced by AT1R antagonist irbesartan,and not influenced by AT2R antagonist CGP42112A. CONCLUSION: These results suggested that left ventricular ATRs upregulate during pressure overload.The left ventricular hypertrophy induced by AngⅡis mainly mediated by AT1R.  相似文献   

2.
AIM: To investigate the effects of angiotensin II (Ang II) and AT1a receptor antagonist (losartan) collagen synthesis in rat hepatic stellate cells (HSCs). METHODS: ① Rat HSCs were isolated, cultured and identified. ② Rat HSCs were incubated in the medium with different concentrations of AngII or losartan, then the quantity of collagen was examined by -proline release assay. RESULTS: ① The yield of HSCs was 2×107-3×107/per rat, their viability and purity was more than 95% and 90%, respectively. ② The yield of collagen in HSCs significantly got a rise in a concentration-dependent manner when HSCs were incubated with AngII (10－6mol/L-10－10 mol/L) (P<0.05). While HSCs were influenced by the antagonist of AT1a (10－6 mol/L-10－9 mol/L), the quantity of collagen dropped greatly (P<0.05). CONCLUSIONS: Ang II stimulates HSCs to produce more collagen. Losartan inhibits the cell to synthesize collagen via AT1a receptor (P<0.05). The results indicate that Ang II may play an important role in the development of hepatic fibrosis, and using AT1a antagonist may offer a new strategy to prevent hepatic fibrosis.  相似文献   

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4.
AIM:To investigate the crosstalk between angiotensin Ⅱ (AngⅡ)-mediated and platelet-derived growth factor (PDGF)-mediated signal transduction in vascular smooth muscle proliferation.METHODS:A model of renal hypertension was made by two kidney/one-clip operation. Level of PDGF receptor β subunit of aorta was measured by Western Blot analysis. The effect of Ang Ⅱ on PDGF receptor β subunit expression was investigated in culture rat aortic vascular smooth muscle cells (VSMC).RESULTS:Systolic blood pressure obviously increased at 8th week after operation, whereas the level of PDGF receptor β subunit of aorta significantly increased by 126.6% (P＜0.05) in 2K1C rats compared with control group. The expression of PDGF receptor β subunit in cultured VSMC stimulated by AngⅡ was higher than that of control by 192.74%(P＜0.01). The effect of AngⅡ was inhibited remarkably by pretreated with losartan, a kind of specific AngⅡ receptor 1 (AT1) subtype antagonist and U73122, a kind of phospholipase C inhibitor. The effect was partly blocked by PD98059, which inhibit the activity of mitogen-activated, ERK-activating kinase (MEK).CONCLUSION:AngⅡ-induced PDGF receptor β subunit expression is regulated by the AT1 and its downstream signal molecule-PLC and ERK, might participate in the intracellular signal transduction pathway.  相似文献   

5.
AIM: To investigate the effects of Ang Ⅱon the production of ET-1, NO from myocardial fibroblasts (MFs) of adult rat. METHODS: MFs were extracted by enzymatic digestion and anchorage velocity-dependent separation method. In this study, the changes of ET-1 and NO production from MFs in the second passage were examined by radioimmunoassay and by nitrate reductase-dependent assay, separatively. RESULTS: In a specific concentration range, AngⅡ increased ET-1 synthesis in MFs in a concentration-dependent manner. Losartan, the antagonist of angiotensin Ⅱ 1 type recepters (AT1R), blocked the above effects. Ang Ⅱ may inhibit NO synthesis in MFs. When MFs were treated with losartan+Ang Ⅱ, the production of NO increased significantly, and was higher than that treated with the others (P<0.01). CONCLUSION: Ang Ⅱ may increase the production of ET-1 in MFs via AT1R and affect NO production in MFs mainly via AT1R to change the ratio of ET-1 and NO. Ang Ⅱ maybe exert inductive effects on myocardial hypertrophy and heart failure by affecting these complicated balances between bioactive factors produced from MFs.  相似文献   

6.
AIM: To evaluate the role of human angiotensin II (AngII) type 1 receptor (AT1R) antisense cDNA (ahAT1) on migration of cultured artery smooth muscle cells (VSMCs). METHODS: Two recombinant adenoviral vectors, Ad/CMV.ahAT1 containing full length antisense cDNA targeting to human AT1R mRNA, and Ad/CMV.LacZ containing LacZ called report gene, were constructed by orientation clone technology and homologous recombination, and then were used to transfect VSMCs in vitro. AT1R expression detected by RT-PCR and immunohistochemistry, and migration of VSMCs measured by Boyden's Chamer methods, were compared between transfected and nontransfected VSMCs. RESULTS: Forty-eight hours after Ad/CMV. ahAT1 transfection, the level of AT1R mRNA decreased markedly (50% of control group), and AT1R protein expression was significantly less (P＜0.01 vs control-group and Ad/CMV.LacZ-group, respectively) in VSMCs. So it was migration distance of VSMCs among the three groups. CONCLUSION: These results indicate that antisense cDNA targeting to human AT1R transfer in vitro mediated by adenoviral vector has a powerful inhibitory effect on migration of VSMCs by attenuating AT1R expression.  相似文献   

7.
AIM: To investigate whether angiotensinⅡ (AngⅡ)/angiotensin Ⅱ type 1 receptor (AT1R) pathway down-regulates endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation level in human umbilical vein endothelial cells by activating protein phosphatase 2A (PP2A).METHODS: Human umbilical vein endothelial cells were randomly divided into normal control (control) group, Ang Ⅱ group, candesartan (CAN; specific AT1R blocker) group and CAN pretreatment+AngⅡ group. The protein levels of total eNOS, p-eNOS (Ser1177), PP2Ac, I2PP2A and p-PP2Ac (Tyr307) were determined by Western blot. The content of NO in the cell culture medium was detected by chemical colorimetry.RESULTS: Compared with control group, the level of p-eNOS (Ser1177) and the content of NO decreased (P<0.05). Compared with the same concentration of AngⅡ group, CAN pretreatment increased the level of p-eNOS (Ser1177) and the content of NO (P<0.05), but the protein expression of eNOS showed no significant difference. Compared with control group, the levels of p-PP2Ac (Tyr307) and I2PP2A decreased (P<0.05). Compared with the same concentration of AngⅡ group, CAN pretreatment increased the levels of p-PP2Ac (Tyr307) and I2PP2A (P<0.05), but the protein expression of PP2Ac showed no significant difference.CONCLUSION: AngⅡ down-regulates the level of p-eNOS (Ser1177), and decreases the production of NO in human umbilical vein endothelial cells via AT1R pathway. This effect may be related to the reduction of p-PP2Ac (Tyr307) and protein expression of I2PP2A, which results in the enhancement of PP2A activity. Pretreatment with AT1R blocker CAN increases p-PP2Ac (Tyr307) level and I2PP2A protein expression, thus reducing the PP2A activity, and ultimately restoring eNOS Ser1177 phosphorylation level and eNOS activity.  相似文献   

8.
AIM:To study the impact of hyperlipidemia on aortic AT1 mRNA expression and vasoactive substances, and investigate the potential mechanism on reversion of endothelial dysfunction during the statin therapy.METHODS:The investigation included control, hyperlipidemic and simvastatin-treated groups. Hyperlipidemic model was set up on the 4-week atherogenic diet, followed by a 16-week treatment in the simvastatin treated group (simvastatin 10 mg·kg-1·d-1) and without treatment in the hyperlipidemic group. Serum lipid level, the expression of AT1mRNA of aorta and level of serum AngⅡ and nitric oxide (NO) were measured. RESULTS: Compared with the control group, hyperlipidemic rats showed a stronger expression of AT1 mRNA and lower level of NO. No significant difference in systolic blood pressure and AngⅡ was showed in this group. In contrast, in simvastatin treated group, expression of AT1 mRNA as well as lipid(TC, TG, LDL-C) levels were significantly decreased and NO level increased which associated with improvement of endothelial dysfunction. CONCLUSION:By regulated the lipid level, downregulated AT1 mRNA expresstion and increased the NO activity, simvastatin restored endothelial function and inhibited atherogenesis.  相似文献   

9.
AIM: To investigate the effect of nucleolin on angiotensin II (Ang II)-induced phenotypic transformation of vascular smooth muscle cells (VSMCs). METHODS: Ang II was used to induce the phenotypic transformation of VSMCs. The spatial and temporal expression patterns of nucleolin, and the effects of Ang II on the expression of VSMC phenotypic transformation markers α-smooth muscle actin (α-SMA), calponin, smooth muscle protein 22 α (SM22α) and osteopontin (OPN) were investigated. The techniques of gene over-expression and RNA interference were used to assess the effect of nucleolin on the expression of Ang II-mediated VSMC phenotypic transformation markers. RESULTS: The expression of α-SMA, SM22α and calponin at the mRNA and protein levels was gradually decreased by Ang II stimulation, while the expression of OPN at mRNA and protein levels was gradually increased. The expression of nucleolin was gradually up-regulated in the VSMCs treated with Ang II at different concentrations for various duration (P<0.05). Ang II induced nucleolin translocation from the nucleus to cytoplasm. Over-expression of nucleolin promoted the VSMC phenotypic transformation induced by Ang II. Down-regulation of nucleolin suppressed the promotion of phenotypic transformation. CONCLUSION: Nucleolin promotes Ang II-induced phenotypic transformation of VSMCs, and its mechanism may be related to its function of cytoplasmic translocation.  相似文献   

10.
AIM: To investigate the role of nephrin, a slit diaphragm-associated protein, in angiotensinⅡ (AngⅡ)-induced cytoskeleton rearrangement in podocytes. METHODS: Immortalized mouse podocytes were exposed to AngⅡ (10-8 mol/L) with or without AngⅡ receptor antagonist lorsatan and Akt inhibitor LY294002. FITC-conjugated phalloidin was used to stain F-actin, and semi-quantitative system with cortical F-actin score (CFS) was introduced to analyze the degree of actin cytoskeleton arrangement. The expression of nephrin was assessed by quantitative real-time RT-PCR,RT-PCR and Western blotting. Undifferentiated podocytes were transfected with pcDNA3.1-mNPHS1 plasmid containing the full length of nephrin. The stably transfected cell line was generated by G418 selection. Phosphorylation level of Akt was assessed by Western blotting, and F-actin distribution was further evaluated in transfected cells exposed to AngⅡ or not. RESULTS: Cytoskeletal rearrangements including cortical F-actin ring formation and stress fiber attenuation were observed in Ang II-and LY294002-stimulated podocytes. Pretreatment with losartan significantly prevented Ang II-induced actin cytoskeleton reorganization. The mRNA and protein levels of nephrin and phosphorylation of Akt were obviously decreased in the podocytes exposed to Ang II, which were dramatically reversed by pcDNA3.1-mNPHS1 transfection. Transfection of pcDNA3.1- mNPHS1 induced the formation of short filopodia and partially prevented AngⅡ-induced F-actin remodeling. CONCLUSION: PI3K/Akt signaling is a common downstream pathway of nephrin and Ang Ⅱ. Nephrin is able to stabilize AngⅡ-induced cytoskeletal rearrangement via PI3K/Akt signaling pathway.  相似文献   

11.
AIM: To investigate the inhibitory effects of fluvastatin on the migration of rat vascular smooth muscle cells (VSMCs) induced by angiotensin II (AngⅡ) and platelet derived growth factor-BB (PDGF-BB). METHODS: Cultured VSMCs derived from rat thoracic aorta were used. The activity of heat shock protein 27 (HSP27) was evaluated by Western blotting with specific phospho-HSP27 antibody. The effect of F-actin polymerization was detected by FITC-phalloidine staining and examined by confocal microscopy. Modified Boyden chamber technique was employed for VSMCs migration assessment. RESULTS: The phosphorylation of HSP27 in VSMCs was increased by the stimulation of AngⅡ and PDGF-BB in a concentration-dependent manner. Treatment with AngⅡ and PDGF-BB resulted in a substantial increase in the number of stress fibers and rearrangement of these structures into ordered parallel arrays. The migration of VSMCs was promoted by AngⅡ and PDGF-BB. Reorganization of actin cytoskeleton stimulated with AngⅡ and PDGF-BB was inhibited by a specific HSP27 inhibitor quercetin (100 μmol/L) pretreatment. The inhibitory rates of 100 μmol/L quercetin on the migration of VSMCs induced by AngⅡ and PDGF-BB were 55.3% and 53.6%,respectively (P<0.01). The phosphorylation of HSP27 in response to AngⅡ and PDGF-BB was suppressed by fluvastatin in a dose-dependent manner, and maximal inhibitory rates were between 42.1% and 58.5% with 10-5 mol/L fluvastatin,respectively (P<0.01).CONCLUSION: Fluvastatin influences the migration of VSMCs in part by inhibiting HSP27 phosphorylation.  相似文献   

12.
AIM: To examine the renal sympathoexcitation affected by microinjection of angiotensin Ⅱ type 1 (AT1) receptor antagonist L-158809 and angiotensin Ⅱ type 2 (AT2) receptor antagonist PD123319 into paraventricular nucleus (PVN) in heart failure rats.METHODS: Left anterior descending coronary artery ligation was used to induce rat heart failure (HF) . Four weeks after operation, the left ventricular end-diastolic pressure (LVEDP), the ratios of heart weight/body weight and lung weight/body weight, and the ratio of infarct area of the left ventricle were observed. Under anesthesia, SD rats were fixed into the brain stereo controller to locate PVN for microinjection and the artificial cerebrospinal fluid (ACSF) was used for control. The left kidney was exposed by retroperitoneal approach and the renal sympathetic nerve was separated under surgical microscope. The heart rate, blood pressure and the activity of renal sympathetic nerve discharge (RSNA) were recorded by POWERLAB 8/30 system. RESULTS: Microinjection of AT1 receptor antagonist into PVN induced a decrease in RSNA in both HF rats and sham rats. The RSNA responses to L-158809 in the HF rats were significantly greater (P<0.05) than those in the sham rats. However, microinjection of AT2 receptor antagonist and ACSF into PVN induced no change of RSNA in both HF and sham rats. CONCLUSION: There are some differences of sympathetic nerve outputs between using AT1 receptor antagonist and AT2 receptor antagonist on PVN, indicating the up-regulation of AT1 receptors in PVN during HF. The central renin-angiotensin-aldosterone system(RAAS) may be affected by AT1 receptor, not by AT2 receptor.  相似文献   

13.
AIM: To investigate the effects of angiotensin II receptor antagonist on remodeling of renal arterioles in hypertension. METHODS: Eighteen 4 weeks old male rats were divided into three groups: Wistar-Kyoto rats (WKY) for normotensive group, and spontaneously hypertensive rats (SHR) for hypertensive group, and SHR treated with losartan orally (15 mg·kg-1·d-1). The rats were raised to 16 weeks old. The morphometric parameters of the renal arterioles, and the widths of vascular smooth muscle cells (VSMC) and intercellular space were studied on kidney slices by light microscope and electromicroscope respectively, combined with computer-assistant image analysis system. The minimal renal vascular resistance (RVRmin) was studied by isolated kidney perfusion system. RESULTS: The systolic blood pressure of the tail artery, wall thickness, wall area, ratio of wall thickness to inner diameter, width of VSMC of renal arterioles and RVRmin were all smaller or lower in losartan group than those of SHR.  相似文献   

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15.
AIM: To investigate the effect of angiotensin II type 1 receptor (AT1R)-calcineurin (CaN) signaling pathway on the expression of sodium current channel Nav1.5 at mRNA and protein levels in the hypertrophic ventricular myocytes from neonatal rats.METHODS: The ventricular myocytes were isolated from the ventricles of 1-day-old neonatal Sprague-Dawley rats and were divided into 4 groups according to different drug intervention as control group, phenylephrine (PE) group, losartan (Los)+PE group and cyclosporin A (CsA)+PE group. The method of RNA interference mediated by adenovirus carrying short hairpin RNA (shRNA) was used to knock down the gene which encodes the beta subtype of CaN A subunit (CnAβ) and the cells were divided into 4 groups as Ad-Null group, Ad-Null+PE group, Ad-CnAβshRNA1 group and Ad-CnAβshRNA1+PE group. The mRNA expression of brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC) and Nav1.5 was detected by RT-qPCR. The protein levels of CnAβ and Nav1.5 in the whole-cell extracts were determined by Western blot analysis.RESULTS: Treatment of the neonatal rat ventricular myocytes with PE for 24 h increased the protein-to-DNA ratio and the mRNA expression of BNP and β-MHC. The size of the cell surface was also increased after PE treatment. Treatment of the cells with PE increased the protein expression of CnAβ, and reduced the protein expression of Nav1.5. Both Los and CsA prevented those effects of PE. The mRNA expression of Nav1.5 was reduced by PE, and no significant difference of Nav1.5 mRNA expression among PE group, Los+PE group and CsA+PE group was observed. Silencing of CnAβ in the neonatal rat ventricular myocytes using Ad-CnAβshRNA1 inhibited the ability of PE to increase the mRNA expression of BNP, and diminished the ability of PE to reduce the protein expression of Nav1.5.CONCLUSION: AT1R-CaN signaling pathway participates in regulating protein expression of Nav1.5 in the hypertrophic ventricular myocytes from neonatal rats.  相似文献   

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18.
AIM:To explore the effects of hydrogen sulfide (H2S) on proliferation of vascular smooth muscle cells (VSMC) stimulated by endothelin (ET-1, 10-7mol/L) and mitrogen-activated protein kinase (MAPK) activity in VSMCs.METHODS:Cultured VSMCs were divided into six groups: (1) control group, (2) serum group, (3) endothelin group, (4) NaHS groups, (5) serum+NaHS group, and (6) endothelin+NaHS group. VSMC proliferation was measured by[3H]-TdR incorporation and MAPK activity in VSMC was determined by radioactivity assay.RESULTS:ET-1 increased VSMC[3H]-TdR incorporation by 2.39 times (P＜0.01) and MAPK activity by 1.62 times(P＜0.01), as compared with control. H2S (5×10-5-5×10-4mol/L) decreased VSMC[3H]-TdR incorporation and MAPK activity by 16.8%-37.4% and 7.4%-33.6%, respectively (P<0.05 or P＜0.01).CONCLUSION:This study demonstrates that H2S inhibits ET-1-induced proliferation of VSMC, which might be mediated by the inhibition of MAPK.  相似文献   

19.
AIM: To observe the effects of angiotensinⅡ (AngⅡ) and angiotensin-(1-7) on the expression of (pro)renin receptor in rat vascular smooth muscle cells.METHODS: The cultured VMSCs were randomly divided into control group, AngⅡ group, Ang-(1-7) group, AngⅡ+losartan (an AT1 receptor antagonist) group, AngⅡ+PD123319(an AT2 receptor antagonist) group and CGP42112A (an AT2 receptor agonist)group. The expression of (P)RR at protein and mRNA levels was detected by Western blotting and real-time PCR,respectively.RESULTS: Compared with control group, AngⅡ distinctly increased and Ang-(1-7) decreased the expression of (P)RR mRNA and protein in VMSCs in a dose-dependent manner (P<0.01). Compared with AngⅡ group, losartan did not inhibit the expression of (P)RR mRNA and protein in VMSCs induced by AngⅡ (P>0.05), but PD123319 did (P<0.01). CGP42112A also induced the expression of (P)RR protein and mRNA in VMSCs (P<0.01).CONCLUSION: AngⅡ induces the expression of (P)RR in VMSCs by AT2. However, Ang-(1-7) inhibits the expression of (P)RR in VMSCs.  相似文献   

20.
AIM:To compare the renoprotective effects of angiotensinⅡtypeⅠreceptor antagonist (AT1RA) with that of angiotensin converting enzyme inhibitor (ACEI) and to investigate their influences on intrarenal renin-angiotensin system. METHODS: Experimental nephrotic syndrome model was induced in SD rats with repeated peritoneal injections of puromycin. Twenty-eight rats were randomly divided into four groups: normal control, nephrotic control, ACEI-treated and AT1RA-treated group. Serum, urine and renal tissue were collected for study 12 weeks later. RESULTS: The urine protein was less and renal function was better in both treated groups. The glomerular and interstitial injury indexes of both ACEI and AT1RA treated rats were lower than that of nephrotic control rats and had no significant difference between the two treated groups. The renal local ACE activity and angiotensinⅡ of nephrotic control group were significantly higher than that of normal control group and the two treated group(P＜0.01). CONCLUSION:AT1RA and ACEI have comparable renal protective effects on nephrotic syndrome and these effects may be related to the inhibition of renal local ANGⅡ.  相似文献   

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