Effects of RHO kinase inhibitors on matrix metalloproteinases-2 and transforming growth factor-β1 in the process of ventricular remodeling
0
Citation
0
Reference
20
Related Paper
Abstract:
Objective To observe the effects of fasudil on levels of plasma MMP-2 and TGF-β1 in patients with chronic heart failure,and investigate the resistance mechanism of RHO kinase inhibitors in the process of ventricular remodeling.Methods Fourty patients with New York Heart Association (NYHA) NYHA Ⅳ were randomly divided into conventional treatment group and fasudil grou.Patients in conventional treatment group were given a formal anti-heart failure treatment according to the American heart failure guidelines,patients in fasudil group additionally received fasudil 60 mg dose intravenous drip qd for two weeks.The levels of plasma MMP-2,TGF-β1,LVEDD,LVEF were measured and compared before and after the treatment between the two groups.Results The MMP-2 and TGF-β1 plasma levels in the two groups decreased significantly after 2 weeks treatment (P ＜ 0.01),and fasudil treatment group was more obvious than conventional treatment group (P ＜ 0.05).Conclusions The patients with chronic heart failure with ventricular remodeled,heart contraction function droped,the MMP-2 and TGF-β1 expression levels increased,both may be involved in the heart failure of ventricular remodeling process.Fasudil can decrease MMP-2 and TGF-β1 expression levels,indicating that fasudil may play the role of ventricular remodeling in heart failure through this way.
Key words:
RHO kinase inhibitors; Heart failure ; Ventricular remodeling; Matrix metalloproteinases 2; Transformation growth factor-β1Keywords:
Fasudil
Rho kinase inhibitor
Ventricular remodeling
Objective: To study the effects of fasudil on heart failure rat models induced by coarctation of ascending aorta. Methods: A model of heart failure induced by coarctation of ascending aorta was used . Fifty female Wistar rats with heart failure were divided randomly into 5 groups (n=10): heart failure (natrii chloridi, 0.1ml), fasudil (1 mg/kg), fasudil (5 mg/kg), fasudil (20 mg/kg), Bid i.p and nifedipine (10 mg/kg). Ten age-matched rats received sham operation were as control. Hemodynamics, ratio of LV weight to body weight, and expression of RhoA and Rho kinase mRNA were investigated in all groups. Results: Level of RhoA and Rho kinase mRNA were higher in heart failure groups than those of control . Fasudil could decrease the expression level of RhoA and Rho kinase mRNA and have dose relationship, nifedipine could not change the expression level of RhoA and Rho kinase mRNA . Conclusion: Heart failure was probably related to the activation of RhoA and Rho kinase. Fasudil may have beneficial effects on heart failure by decreasing the expression of RhoA and Rho kinase mRNA. Fasudil may be a novel and potent vasodilator for the treatment of heart failure.
Fasudil
Rho kinase inhibitor
Cite
Citations (0)
Objective To investigate the influence of valsartan(angiotension Ⅱ type I receptor antagonist) on the levels of serum transforming growth factor-beta1(TGF-β1),matrix metalloproteinase-1(MMP-1),tissue inhibitors of metalloproteinase-1(TIMP-1) in patients with essential hypertension(EH) and on reversing left ventricular hypertrophy(LVH).Methods The 58 patients with EH and LVH identified by Dopple echocardiography were treated with valsartan.Before and after treatment for 6 months,left ventricle mass index(LVMI) and serum levels of TGF-β1,MMP-1,TIMP-1 were obtained and analyzed respectively.Serum levels of TGF-β1 and MMP-1 and TIMP-1 were measured by sandwich assay-enzyme linked immunosorbent assay(ELISA) and indirect-ELISA respectively.Results LVMI value of patients was significantly decreased after treatment with valsartan(P0.01),serum level of TGF-β1 was significantly decreased and level of MMP-1 was significantly increased correspondingly(P0.01 and P0.05 respectively).Level of TGF-β1 was negatively correlated with level of MMP-1(γ=-0.5571,P0.01).Conclusions TGF-β1 may inhibit the expression of MMP-1 and cause LVH in patients with EH and valsartan reverses LVH possibly by decreasing the expression of TGF-β1 and increasing the level of MMP-1.
Essential hypertension
Cite
Citations (0)
Objective: To evaluate the effect of Fasudil on cardiac structure and function in diabetes-atherosclerosis rats with the related mechanism. Methods: A total of 25 Wista rats were randomly divided into 3 groups, Control group, n=5, the rats received normal diet, Model group and Fasudil group, n=10 diabetes-atherosclerosis rats in each group, and the animals respectively received normal saline and fasudil for 4 weeks. By the end of treatment, the echocardiogram, blood levels of vWF, ET-1 and left myocardial tissue pathology were examined and compared among different groups. Results: ① Compared with Control group, Model group had increased end-diastolic inter ventricular septum thickness, end-diastolic left ventricular thickness, left ventricular end-diastolic dimension(LVEDd), LVESd and left ventricular weight index by echocardiogram, all P0.05; there were no real differences between Fasudil and Control groups, P0.05; while those indicators were lower in Fasudil group than those in Model group, P0.05. ② Compared with Control group, Model and Fasudil groups showed higher levels of vWF and ET-1(P0.05 between Model and Control groups, P0.05 between Fasudil and Control groups); the above indexes in Fasudil group were lower than those in Model group, P0.05. ③ Tissue pathology indicated that myocardial congestion, swelling and necrosis were less severe in Fasudil group than Model group. Conclusion: The diabetes-atherosclerosis rats have myocardial injury and left ventricular remodeling. Fasudil could improve vascular endothelial function, and therefore, play the anti-atherosclerosis role and inhibiting ventricular remodeling.
Fasudil
Ventricular remodeling
Cite
Citations (0)
OBJECTIVE To investigate the effect of vasopeptidase inhibitor on ventricular remodeling,cardiac function,tumor necrosis factor-α protein and matrix metalloproteinase-2 after myocardial infarction in rats.METHODS Male Sprague-Dawley(SD) rats were randomly divided into three groups: sham,MI and MI + omapatrilat(OMA).Myocardial infarction was produced by ligation of the left anterior descending coronary artery.After 24 hours of operation,rats in the MI + OMA group were treated with 40 mg·kg~(-1)·d~(-1) OMA in their drinking water,and rats in the sham and MI groups were treated with placebo.Determine the hemodynamic and ventricular index as well as the expression of TNF-α protein and MMP2 protein at 6 weeks after operation.RESULTS The expression of TNF-α protein and MMP-2 protein in the non-infarcted zone were significantly increased in MI group than in sham group.OMA significantly reduced TNF-α protein and MMP-2 protein expression,improved ventricular function and ventricular remodeling.CONCLUSION The vasopeptidase inhibitor shows favorable effects on left ventricular remodeling after MI in rats and improves cardiac function.These effects could be relevant to the attenuation of increased MMP-2 and TNF-α in left ventricular.
Ventricular remodeling
Cite
Citations (0)
Objective To investigate the expressions of connective tissue growth factor(CTGF) and transforming growth factor-β1(TGF-β1) in pulmonary vascular,and to find if fasudil,a Rho kinase inhibitor,has protective effect on this high blood flow induced pulmonary hypertension model and its possible mechanism.Methods The rat model of pulmonary hypertension was established by right carotid artery-external jugular vein shunt operation.75 male Wister rats were randomly divided into the control group,the 2-week shunt model group,the 4-week shunt model group,the 2-week fasudil group and the 4-week fasudil group(15 in each group).The right ventricle systolic pressure(RVSP) and small pulmonary arterial morphologic changes in each group were studied with a microscope for morphometric analysis.The Expressions of CTGF and TGF-β1 were investigated by Western blot and immunohistochemistry.Results Pulmonary arterial morphologic changes in the 2 shunt groups showed that WT%,RVSP,CTGF expression and TGF-β1 expression increased significantly.However in the 2 fasudil groups,CTGF and TGF-β1 expressions deceased more significantly than in the corresponding shunt groups.Conclusion Fasudil may partly prevent the development of pulmonary hypertension and pulmonary vascular remodeling and decrease expressions of CTGF and TGF-β1 in high flow induced pulmonary hypertension.
Fasudil
Ventricular pressure
Cite
Citations (0)
Objective:To explore the effect of fasudil on the inflammatory cytokine expression in rats heart following acut myocardial infarction(AMI) and its relationship with the Rho kinase.Method:The model of AMI rats were divided into two groups,treated group(F group) and AMI group,besides another group of sham-operation(S group).Fasudil 5 mg/kg were given into the F group twice a day.The AMI and Sgroup were given equivalent normal saline.Nikon 4 multi-channel physiological recorder records hemodynamics parameters.Radioimmunoassay detected Serum cytokines.EvensBlue and NBT staining identify ischemia and infarction area.The Rho kinase mRNA expression was measured by RT-PCR.Result:Compared with the S group,TNF-α,IL-1β and left ventricular end diastolic pressure(LVEDP) expression in AMI group are significantly higher,the left ventricular systolic pressure(LVSP) and left ventricular pressure rise/fall maximum rate(±dP/dtmax) are significantly lower(P0.05).Compared with the AMI group,F group significantly reduced infarct size,TNF-α and IL-1β and Rho-kinase mRNA expression levels.In F group,there were significant reduction in LVEDP,increased LVSP and ±dp/dtmax(P0.01),and better left ventricular function.Conclusion:Fasudil reduced myocardial infarction myocardial Rho kinase and inflammatory cytokine expression,and improved heart function.The effect of Fasudil on inflammatory factors expression and cardiac function may be related to inhibition of Rho kinase activation.
Fasudil
Preload
Ventricular pressure
Ventricular remodeling
Cite
Citations (0)
Matrix metalloproteinase (MMP) plays a critical role in the development of ventricular remodeling after acute myocardial infarction (AMI). Imidapril, an angiotensin-converting enzyme inhibitor, has been shown to inhibit MMP activity. We investigated whether imidapril inhibits plasma MMP activities and attenuates ventricular remodeling in patients with AMI in comparison with enalapril. We enrolled 70 patients with AMI. All patients underwent primary percutaneous coronary intervention and were randomly assigned either to imidapril (n = 35) or to enalapril (n = 35) treatment. Left ventriculography was performed in acute (day 14) and chronic (6 months) phases, and plasma MMP-2 and MMP-9 activities were measured by zymography. Any changes in left ventricular end-diastolic volume index and ejection fraction from acute to chronic phases did not differ between the 2 groups. The plasma MMP-2 and MMP-9 activities at day 14 were both significantly decreased compared with those at day 1 in both groups (all P < 0.05). At 6 months, MMP-9 activity still remained decreased in both groups (P < 0.05 vs. day 1). Overall, there were no differences between the 2 groups both in plasma MMP-2 and MMP-9 activities. These results demonstrate that imidapril exerts inhibitory effects on plasma MMP activities and attenuates left ventricular remodeling in patients with AMI similar to enalapril.
Ventricular remodeling
Cite
Citations (14)
OBJECTIVE To observe the pharmacological effect of carvedilol on the expression of myocardium tumor necrosis factor-α (TNF-α) mRNA and protein and matrix metalloproteinase(MMP) mRNA and the activity in post-infarction rats. METHODS Rats surviving 24 h after AMI induced by left anterior descending branch ligation were randomized to carvedilol and control group compared with sham-operated group. Carvedilol group were given carvedilol 10 mg·(kg·d) -1.Control and sham-operated group were given saline 15 mL·(kg·d) -1.Observe the hemodynamic and ventricular remodeling index, the expression of myocardium TNF-α mRNA and protein and MMP-2, MMP-9 mRNA and the activity in all groups at the end of the fourth week. RESULTS The expression of myocardium TNF-α mRNA and protein, MMP-2 and MMP-9 mRNA and the activity were all increased in the AMI rats at 4 weeks compared with the sham-operated group. MMP-9 mRNA and activity were all positively correlated with TNF-α protein expression (r= 0.52, P 0.01)(r= 0.73,P 0.01).Treatment with carvedilol reduced the TNF-α mRNA and protein expression as well as MMP-2 and MMP-9 mRNA and the activity level and was associated with the amelioration of the hemodynamics and ventricular remodeling. CONCLUSION TNF-α and MMPs are involved in left ventricular remodeling after AMI. TNF-α may promote the gene expression and activity of MMP. The pharmacological effect of carvedilol of reduction in both myocardium TNF-α and MMP may be one of the beneficial effects of carvedilol on ventricular remodeling.
Carvedilol
Ventricular remodeling
Cite
Citations (0)
Right ventricular hypertrophy
Hypoxia
Cite
Citations (6)
Effects of Metoprolol on Cardiac Extracellular Matrix Remodeling in Acute Myocardial Infarction Rats
Objective:To investigate the roles of metalloproteinase(MMP-2),tissue inhibitor of metalloproteinase(TIMP-2) and transforming growth factorβ1(TGF-β1) in extracellular matrix remodeling after acute myocardial infarction and effects of Metoprolol on it in a rat model.Methods: Rats surviving 24h after AMI induced by left anterior descending branch ligation were randomized to Metoprolol and control groups compared with sham-operated group.Metoprolol group were given Metoprolol 50 mg/(kg·d).Control and sham-operated group were given saline 15 ml/(kg·d).The ventricular remodeling index,the expression of myocardium MMP-2,TIMP-2 and TGF-β1 proteins were observed or examined by immunohistochemical analysis in the AMI rats at 4 weeks.Results: Compared with sham-operated rats,the protein expression of MMP-2,TIMP-2 and TGF-β1 and MMP-2/TIMP-2 ratio were significantly increased(P0.01),while left ventricular(LV) end diastolic pressure(LVEDP),LV relative weight(LVRW),right ventricular relative weight(RVRW) and collagen volume fraction(CVF) were significantly increased(all P0.01);whereas-dp/dt,+dp/dt were significantly reduced(P0.01) at 4 weeks after AMI,indicating decreased LV remodeling and LV function.After four-week metoprolol treatment,the protein expression of MMP-2,and TGF-β1 and MMP-2/TIMP-2 ratio were significantly reduced,respectively from 0.281,0.253 and 1.836 to 0.153,0.128 and 1.006(all P0.01),while left ventricular(LV) end diastolic pressure(LVEDP),LV relative weight(LVRW),right ventricular relative weight(RVRW) and collagen volume fraction(CVF) were significantly reduced by 36.13%,9.56%,9.95% and 29.06%(all P0.01),whereas-dp/dt,+dp/dt were significantly increased by 8.90%,9.64%(all p 0.01) at 4 weeks after AMI.Conclusion: Metoprolol may prevent left ventricular extracellular matrix remodeling,which is associated with the attenuation of myocardial MMP-2 and TGF-β1 and the reversion of MMP-2/TIMP-2 balance.
Preload
Ventricular remodeling
Ventricular pressure
Cite
Citations (0)