刺五加叶皂苷对实验性心室重构的影响及其机制研究
摘要
心室重构贯穿于急性心肌梗死整个疾病发展过程中,急性心肌梗死后的心力衰竭、心律失常的发生与心室重构密切相关。心室重构能全面影响心室的功能状态及生存预后,抑制急性心肌梗死后的心室重构、改善心室功能的研究逐渐成为国内外心血管疾病研究的重点和热点之一。本实验观察ASS对心室重构的影响及其可能的机制。结果表明,ASS能改善心肌梗死后左心室收缩和舒张功能,防止急性心肌梗死后左心室扩张和肥厚,减小室壁切应力,降低重构心肌AngⅡ、E含量及ACE活性,亦能明显降低血清LPO含量及ACE活性,提高SOD、CAT、GSH-Px活性,这对于预防或逆转心室重构具有重要意义。同时ASS可抑制VSMC的增殖,抑制作用与药物剂量呈正比,ASS抑制VSMC增殖机制可能与下调原癌基因的表达和细胞周期阻滞有关。上述结果提示ASS可能通过抑制心脏RAS系统,阻断了AngⅡ及CA的促生长增殖作用,同时抑制了心肌立早基因的表达,抑制心肌细胞肥大发挥防治心室重构的作用。
本文循着前期研究的工作思路观察到ASS抑制心室重构的作用与临床常用的血管紧张素转化酶抑制剂(ACEI)福辛普利相一致,首次提出ASS可能是一种ACE抑制剂,扩展了对其作用机制的认识,为进一步开发利用ASS展示了广阔的前景。
Ventricular Remodeling (VR) runs through the entire developing procession of Acute Myocardial Infarction (AMI), VR is closely related to the development of Cardia Failure (CF) and Cardiacarrhythmia (CA), which occur after AMI. The functional status of cardiac ventricle and existing prognosis are fully affected by VR, the research on VR(after AMI’s inhibition) and improving ventricular function, is gradually becoming one of the focal points of the domestic and international study for cardiovascular diseases. Acanthopanax Senticosus Saponins (ASS) are purified from leaves of Acanthopanax senticosus, which includes 16 kinds of saponin components, 13 kinds of ginsenosides are first purificated in the world. ASS has the funtion of anti-inflammatory, anti-fatigue, anti-stress and increasing organizations’tolerance for hypoxia-ischemia, vascular expansion, est.
We observed the effect and mechanism of ASS to VR and related gene expression, through the rat model of Myocardial Infarction(MI) and cardialcytes hypertrophy and cardiac fibroblasts proliferation model in cell.
1. The effect and mechanism of MI induced VR by ASS
(1) Methods:
Rats were divided into Sham operation group, MI model group, MI / positive drug group and MI/ASS 25mg/kg group, MI/ASS 50mg/Kg group, MI/ASS 100 mg/Kg group. Rats were made MI by ligating Left anterior descending coronary artery. And they were given drugs in accordance with the corresponding groups for 4 weeks. 10 rats from each group were anesthesized through intraperitoneal injection, right common carotid artery was separated after regularing, the 1mm diameter plastic pipe was inserted into the left ventricle, hemodynamic parameters measured. Rats were injected 10% KCL 2-3 ml through femoral vein after Hemodynamic parameters measured, so cardioplegia in ventricular end-diastolic. Rapid thoracotomy, heart was fixed by formalin, for determination of Morphological parameters and Pathology analysis of heart. Blood were taken through Abdominal aortic intubation in each group,for measuring serum malondialdehyde (MDA) content, superoxide dismutase (SOD), catalase (CAT), activity of glutathione peroxidase (GSH-Px). The left ventricular muscle of rats were prepared for Homogenates after checking the heart, Supernatant were taken after Centrifugation, for measuring content of norepinephrine (NE) and epinephrine (E) content through improved fluorescence, content of angiotensinⅡ(Ang
Ⅱ) through RIA [6].
(2) Result:
1) Compared with the sham-operated group, the amount of SBP, DBP, MAP, LVSP,±dp/dtmax and the Calibration (±dp/dtmax/LVSP) in MI group were significantly decreased, LVEDP were significantly increased.
Compared with MI model group,±dp/dtmax and±dp/dtmax/LVSP were significantly increased in MI/ASS 50, 100mg/kg group, LVEDP were significantly decreased in MI/ASS 25, 50, 100mg/Kg group, Also LVSP was lower in ASS 100mg/kg group, SBP, DBP, MAP and HR were no significant effected in ASS three-dose groups.
2) Compared with sham-operated group, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW were significantly increased in MI model group Compared with MI model group, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW were significantly lower in ASS 50, 100 mg/kg group, but no significant effect on BW.
3) Compared with the MI model group, serum LPO‘scontent can be significantly reduced, serum SOD, CAT, GSH-Px activity cloud be improved in ASS 50, 100 mg/kg group LPO‘s content could be significantly reduced, and activity of SOD was improved inASS 25mg/kg group, but no significant effect on the activity of CAT, GSH-Px
4) Compared with MI model group, content of myocardial AngⅡand E could be significantly lower, content of myocardial NE has a reducing trend, in ASS 50, 100 mg/kg group.
5) Compared with MI model group, activity of myocardial ACE could be a significant reduction in ASS 50, 100 mg/kg group, Also significantly decreasing of the activity of serum ACE in ASS 100mg/kg group.
6) In general and endoscopic observation, 4 weeks after AMI, in ASS 100mg/kg group, there is no thinning and expansion in infarciton zone, ventricular septal of non-infarct area and left ventricular wall were thickening apparently, but without expansion of the cavity, which showed concentric hypertrophy, The pathological changes in ASS 25, 50 mg/kg group is similar to MI model group, but the level was significantly lightened; left ventricular shape’s change in Fosinopril group is similar with ASS 100mg/kg group.
2. The research on the effect and mechanism of inhibition of Vascular Smooth Muscle Cell (VSMC) proliferation by ASS
(1) Methods
Rat’s thoracic aortic VSMC were cultured through Attachment-block method. Cells were randomly divided into 5 groups: control group: normal VSMC, AngII model group: AngII 10-7mol/L, ASS low dose group: ASS 25μg/ml+AngII10-7mol/L, ASS Medium dose group: ASS 50μg/ml+AngII10-7mol/L ASS high dose group: ASS 100μg/ml+AngII10-7mol/L.
Cell proliferation cap- acity was determinated through MTT colorimetric micro-enzyme reaction (MTT method).Cell cycle and cell proliferation index were measured by flow cytometry (FCM). c-myc, c-fos and c-jun mRNA expression were measured by RT-PCR.
(2) Result:
1) The effect of ASS on VSMC proliferation, compared with blank control group, OD values was significantly higher in AngII model group s. ompared with AngII c model group, OD values were significantly decreased in ASS 50, 100μg/mlgroup.
2) The effect of ASS on PI and cell cycle of VSMC, in AngII model group, the percentage of VSMC in G0/G1 phase was significantly reduced, and percentage of VSMC in S phase and G2/M phase was significantly increased, PI is also significantly increased.
Compared with AngII model group, in ASS 25, 50, 100μg/ml group, the percentage of VSMC in G0/G1 phase was significantly increased, percentage of VSMC in S phase and PI were significantly decreased,.In ASS 50, 100μg/ml group percentage of VSMC in G2/M phase was significantly lower.
3) The effect of ASS on expression of the proto-oncogene c-myc, c-fos and c-jun mRNA, compared with blank control group, in AngII model group, brightness of bands of c-myc, c-fos and c-jun were significantly strengthened, expression sign- ificantly increased. Compared with AngII model group, in ASS 25, 50, 100μg/ml group, brightness of bands of c-myc and c-jun were significantly weaker, expression were decreased significantly. In ASS 50, 100μg/ml group, brightness of bands of c-fos band was also Obviously weaker, expression decreased significantly.
3. Conclusion
1) In experimental MI induced VR rats, left ventricular systolic and diastolic function can be significantly improved by ASS, which could be effective in preventing left ventricular hypertrophy and expansion after AMI.
2) The mechanism of ASS intervened VR may be related to inhibition of cardiac RAS system, which blocked the AngⅡand the CA's role in promoting the growth and proliferation.
3) ASS can inhibit VSMC proliferation, inhibition was directly proportional to drug dose.The mechanism of inhibition of VSMC proliferation by ASS may be related to the expression of reduced proto-oncogene c-myc, c-fos, c-jun.
本文循着前期研究的工作思路观察到ASS抑制心室重构的作用与临床常用的血管紧张素转化酶抑制剂(ACEI)福辛普利相一致,首次提出ASS可能是一种ACE抑制剂,扩展了对其作用机制的认识,为进一步开发利用ASS展示了广阔的前景。
Ventricular Remodeling (VR) runs through the entire developing procession of Acute Myocardial Infarction (AMI), VR is closely related to the development of Cardia Failure (CF) and Cardiacarrhythmia (CA), which occur after AMI. The functional status of cardiac ventricle and existing prognosis are fully affected by VR, the research on VR(after AMI’s inhibition) and improving ventricular function, is gradually becoming one of the focal points of the domestic and international study for cardiovascular diseases. Acanthopanax Senticosus Saponins (ASS) are purified from leaves of Acanthopanax senticosus, which includes 16 kinds of saponin components, 13 kinds of ginsenosides are first purificated in the world. ASS has the funtion of anti-inflammatory, anti-fatigue, anti-stress and increasing organizations’tolerance for hypoxia-ischemia, vascular expansion, est.
We observed the effect and mechanism of ASS to VR and related gene expression, through the rat model of Myocardial Infarction(MI) and cardialcytes hypertrophy and cardiac fibroblasts proliferation model in cell.
1. The effect and mechanism of MI induced VR by ASS
(1) Methods:
Rats were divided into Sham operation group, MI model group, MI / positive drug group and MI/ASS 25mg/kg group, MI/ASS 50mg/Kg group, MI/ASS 100 mg/Kg group. Rats were made MI by ligating Left anterior descending coronary artery. And they were given drugs in accordance with the corresponding groups for 4 weeks. 10 rats from each group were anesthesized through intraperitoneal injection, right common carotid artery was separated after regularing, the 1mm diameter plastic pipe was inserted into the left ventricle, hemodynamic parameters measured. Rats were injected 10% KCL 2-3 ml through femoral vein after Hemodynamic parameters measured, so cardioplegia in ventricular end-diastolic. Rapid thoracotomy, heart was fixed by formalin, for determination of Morphological parameters and Pathology analysis of heart. Blood were taken through Abdominal aortic intubation in each group,for measuring serum malondialdehyde (MDA) content, superoxide dismutase (SOD), catalase (CAT), activity of glutathione peroxidase (GSH-Px). The left ventricular muscle of rats were prepared for Homogenates after checking the heart, Supernatant were taken after Centrifugation, for measuring content of norepinephrine (NE) and epinephrine (E) content through improved fluorescence, content of angiotensinⅡ(Ang
Ⅱ) through RIA [6].
(2) Result:
1) Compared with the sham-operated group, the amount of SBP, DBP, MAP, LVSP,±dp/dtmax and the Calibration (±dp/dtmax/LVSP) in MI group were significantly decreased, LVEDP were significantly increased.
Compared with MI model group,±dp/dtmax and±dp/dtmax/LVSP were significantly increased in MI/ASS 50, 100mg/kg group, LVEDP were significantly decreased in MI/ASS 25, 50, 100mg/Kg group, Also LVSP was lower in ASS 100mg/kg group, SBP, DBP, MAP and HR were no significant effected in ASS three-dose groups.
2) Compared with sham-operated group, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW were significantly increased in MI model group Compared with MI model group, LVV, LVLA, LVSA, LVAW, LVRW, RVAW and RVRW were significantly lower in ASS 50, 100 mg/kg group, but no significant effect on BW.
3) Compared with the MI model group, serum LPO‘scontent can be significantly reduced, serum SOD, CAT, GSH-Px activity cloud be improved in ASS 50, 100 mg/kg group LPO‘s content could be significantly reduced, and activity of SOD was improved inASS 25mg/kg group, but no significant effect on the activity of CAT, GSH-Px
4) Compared with MI model group, content of myocardial AngⅡand E could be significantly lower, content of myocardial NE has a reducing trend, in ASS 50, 100 mg/kg group.
5) Compared with MI model group, activity of myocardial ACE could be a significant reduction in ASS 50, 100 mg/kg group, Also significantly decreasing of the activity of serum ACE in ASS 100mg/kg group.
6) In general and endoscopic observation, 4 weeks after AMI, in ASS 100mg/kg group, there is no thinning and expansion in infarciton zone, ventricular septal of non-infarct area and left ventricular wall were thickening apparently, but without expansion of the cavity, which showed concentric hypertrophy, The pathological changes in ASS 25, 50 mg/kg group is similar to MI model group, but the level was significantly lightened; left ventricular shape’s change in Fosinopril group is similar with ASS 100mg/kg group.
2. The research on the effect and mechanism of inhibition of Vascular Smooth Muscle Cell (VSMC) proliferation by ASS
(1) Methods
Rat’s thoracic aortic VSMC were cultured through Attachment-block method. Cells were randomly divided into 5 groups: control group: normal VSMC, AngII model group: AngII 10-7mol/L, ASS low dose group: ASS 25μg/ml+AngII10-7mol/L, ASS Medium dose group: ASS 50μg/ml+AngII10-7mol/L ASS high dose group: ASS 100μg/ml+AngII10-7mol/L.
Cell proliferation cap- acity was determinated through MTT colorimetric micro-enzyme reaction (MTT method).Cell cycle and cell proliferation index were measured by flow cytometry (FCM). c-myc, c-fos and c-jun mRNA expression were measured by RT-PCR.
(2) Result:
1) The effect of ASS on VSMC proliferation, compared with blank control group, OD values was significantly higher in AngII model group s. ompared with AngII c model group, OD values were significantly decreased in ASS 50, 100μg/mlgroup.
2) The effect of ASS on PI and cell cycle of VSMC, in AngII model group, the percentage of VSMC in G0/G1 phase was significantly reduced, and percentage of VSMC in S phase and G2/M phase was significantly increased, PI is also significantly increased.
Compared with AngII model group, in ASS 25, 50, 100μg/ml group, the percentage of VSMC in G0/G1 phase was significantly increased, percentage of VSMC in S phase and PI were significantly decreased,.In ASS 50, 100μg/ml group percentage of VSMC in G2/M phase was significantly lower.
3) The effect of ASS on expression of the proto-oncogene c-myc, c-fos and c-jun mRNA, compared with blank control group, in AngII model group, brightness of bands of c-myc, c-fos and c-jun were significantly strengthened, expression sign- ificantly increased. Compared with AngII model group, in ASS 25, 50, 100μg/ml group, brightness of bands of c-myc and c-jun were significantly weaker, expression were decreased significantly. In ASS 50, 100μg/ml group, brightness of bands of c-fos band was also Obviously weaker, expression decreased significantly.
3. Conclusion
1) In experimental MI induced VR rats, left ventricular systolic and diastolic function can be significantly improved by ASS, which could be effective in preventing left ventricular hypertrophy and expansion after AMI.
2) The mechanism of ASS intervened VR may be related to inhibition of cardiac RAS system, which blocked the AngⅡand the CA's role in promoting the growth and proliferation.
3) ASS can inhibit VSMC proliferation, inhibition was directly proportional to drug dose.The mechanism of inhibition of VSMC proliferation by ASS may be related to the expression of reduced proto-oncogene c-myc, c-fos, c-jun.
引文
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