| Animal experiments and clinical observations have shown that pharmacological interventions to inhibit cardiac hypertrophy and fibrosis can delay the deterioration of cardiac function.Angiotensin Ⅱ(Ang Ⅱ)is the main bioactive peptide derived from the renin-angiotensin-aldosterone system.Through interacting with Ang Ⅱ type 1 receptor(AT1R),Ang Ⅱ plays an important role in the physiological and pathological regulation of cardiovascular function.Although angiotensin-converting enzyme inhibitors and AT1 receptor blockers have been routinely used in clinical practice,and achieved good therapeutic outcomes,the observations from patients suggest that the use of such drugs also causes a range of side effects.Therefore,adjunctive therapies to reduce cardiac remodeling and promote cardiac recovery through modulating the Ang Ⅱ system still merits further investigation.Glucagonlike peptide 1(GLP-1)is an intestinal hypoglycemic hormone with a short half-life in the body.The exogenous supply of GLP-1 synergistic agent liraglutide has been widely used in the treatment of diabetic patients.In recent years,liraglutide has been also used for the treatment of hypertension,myocardial infarction,cardiomyopathy and a variety of other cardiovascular diseases,which is independent of its hypoglycemic regulatory mechanisms.However,there is still a lack of systematic evaluation and exploration on the efficacy and mechanism of liraglutide in the treatment of pressure overload induced heart failure.Therefore,this study selected an in vivo rat model of abdominal aortic constriction,and observed the intervention characteristics of liraglutide on pressure overload induced Ang Ⅱ activation(study part I),which include 1)myocardial oxidative stress and antioxidant enzymes;2)regulation of Ang Ⅱ AT1/AT2 receptor balance;3)the influence of fibroblast migration and proliferation;4)regulation of myocardial hypertrophy and systolic/diastolic dysfunction.In order to understand the potential regulatory mechanisms,the action link of liraglutide therapeutic efficacy were further analyzed(study part Ⅱ),including 1)demonstration of blood GLP-1 level;2)heart morphology and heart/body weight ratio;3)influence of fibrosis response regulating protein expression such as mTOR/p70S6K;4)expression of autophagy regulating proteins such as LC3,beclin-1 and p62;5)regulation of myocardial fibrosis and cardiac function changes.In cultured H9C2 cardiac muscle cells,direct effect of liraglutide on Ang Ⅱ induced changes in cell reaction characteristics were demonstrated(study part ⅡI).These were 1)the observation of cell proliferation and hypertrophy;2)regulation in the expression of Ang Ⅱ AT1/AT2 receptors and regulation of cellular oxidation response levels such as ROS and fibrosis levels of TGFβ1 and α-SMA;3)regulation in the expression of fibrosis response regulating protein such as mTOR,p-mTOR,p70S6 K,p-p70S6K;4)change in expression of collagen.To clarify the mechanism of action underlying liraglutide regulated Ang Ⅱ receptor and inflammatory response,the Ang Ⅱ AT1 receptor blocker telmisartan and the mTOR specific inhibitor rapamycin were selected to confirm the direct effect of liraglutide on Ang Ⅱ receptor and fibrosis process in all experiments.The results of this study indicated that GLP-1 therapy has a significant inhibitory effect on pressure overload induced myocardial fibrosis and dysfunction.The beneficial effects of liraglutide were achieved through regulating Ang Ⅱ receptors,fibrosis response.These results also provide a new experimental basis and application prospect for the treatment of patients with heart failure with GLP-1 analogs.Part 1:Liraglutide attenuates cardiac remodeling and improves heart function after abdominal aortic constriction through blocking angiotensin Ⅱ type 1 receptor in ratsObjective: Angiotensin Ⅱ(Ang Ⅱ)is known to contribute to the pathogenesis of heart failure by eliciting cardiac remodeling and dysfunction.The glucagon-like peptide-1(GLP-1)has been shown to exert cardioprotective effects in animals and patients.This study investigates whether GLP-1 receptor agonist liraglutide inhibits abdominal aortic constriction(AAC)-induced cardiac fibrosis and dysfunction through blocking Ang Ⅱ type 1 receptor(AT1R)signaling.Methods: 1.Experimental group: Male SD rats were observed for 16 weeks after abdominal aortic constriction(AAC)surgery(n=6 in each group).1)Sham control: rats underwent the same surgical procedure without banding the aorta;2)AAC: rats were produced abdominal aortic constriction(AAC)surge for 16 weeks;3)liraglutide treatment: rats were received a subcutaneous injection of liraglutide at a dose of 0.3 mg/kg twice daily after AAC;4)telmisartan treatment: rats were administered telmisartan via gastric gavage at a dose of 10 mg/kg/day after AAC.2.Rat body weight and blood glucose value were measured every 2 weeks.3.At the end of the experiment,the rat heart was rapidly removed and calculated the heart/body weight index(HW/BW).The MSA of cardiomyocytes was measured after conventional HE staining.4.enzyme-labeled instrument detection: The level of MDA and NT-pro BNP was measured with an MDA detection kit and the NT-pro BNP detection kit.SOD activity a SOD detection kit was determined with a SOD detection kit.5.Immunohistochemical staining for ACE2,macrophages,myofibroblasts and TGF-β1.6.Detection of tissue fibrosis by Masson’s trichrome staining.7.Expression of AT1 R,AT2R,TGF-β1,p-Smad2,Smad2,p-Smad3,Smad4,Smad7,collagen I and collagen Ⅲ by Western blot assay.8.Evaluation of global cardiac function by echocardiography.9.The HR,MAP and left ventricular hemodynamics were pressure via a BL-410 biological signal acquisition and processing system.Results: 1.Effects of liraglutide and telmisartan on body weight and blood glucose after AAC The body weight and blood sugar were monitored every two weeks starting from the second week of the observation.No statistically significant difference in these two parameters was found between each groups although both values have increased.2.Effects of liraglutide and telmisartan on cardiac hypertrophy and heart/body weight ratio after AAC the MSA in the AAC group increased significantly relative to the Sham group(1512±99 vs.586±98μm2,p<0.05).Treatment with liraglutide or telmisartan comparatively reduced the MSA to 766±61 μm2 or 871±51 μm2(all p<0.05 vs.AAC group).Relative to the sham group,AAC group significantly increased the HW/BW ratio relative to the Sham group(3.38±0.17 vs.2.46±0.05,p<0.05),which was significantly reduced by liraglutide or telmisartan(2.63±0.09 and 2.77±0.05 vs.AAC group,all p<0.05).3.Effects of liraglutide and telmisartan on the degree of heart failure after AAC AAC significantly increased NT-pro-BNP level at 16-weeks of observation relative to the sham animals,which were reduced by liraglutide(14.8±1.3 pg/ml)and telmisartan(10.3±0.8 pg/ml)compared with AAC group(48.4±8.6 pg/ml),respectively,all p<0.05.4.Effects of liraglutide and telmisartan on oxidative stress and antioxidant enzyme after AAC AAC significantly increased MDA(23.4±1.3 vs.16.3±0.6 nmol/mg,p<0.05)and reduced SOD(8.1±0.8 vs.10.4±0.4 U/mg,p<0.05)compared with the Sham group.Relative to the AAC group,administration of liraglutide or telmisartan reduced MDA level to 15.9±1.6 and 17.2±1.4 nmol/mg(all p<0.05 vs.AAC group),respectively,and increased SOD enzyme activity by 11.9±1.2 and 11.6±1.1 U/mg,all p<0.05 vs.AAC group).5.Effects of liraglutide and telmisartan on expression of AT1 R,AT2R,AT1R/AT2 R ratio and ACE2 after AAC At the end of 16-weeks of AAC,relative to the sham control,the protein level of the AT1 R was significantly increased by 10.55±2.5%,and the protein expression of the AT2 R was decreased by 36.43±5.6%,all p<0.05,whereas the expression patterns of AT1 R and AT2 R in the liraglutide and the telmisartan groups were reversed,as evidenced by an reduced AT1R/AT2 R ratio.The expression of ACE2 in the perivascular and interstitial myocardium is significantly attenuated in the AAC group relative to the Sham group.Relative to the AAC group,administration of liraglutide or telmisartan preserved the expression of ACE2 at week 16.6.Effects of liraglutide and telmisartan on the macrophage infiltration and TGF-β1 expression The results showed that in the AAC group,the large number of macrophages is recruited in the peri-vascular region and interstitial myocardium at week 16,which was attenuated by treatment with liraglutide or telmisartan.The expression of TGF-β1 in the myocardium was also significantly increased.Administration of liraglutide or telmisartan during AAC comparatively reduced the infiltration of macrophages and expression of TGF-β1 at week 16 compared with the AAC group.7.Effects of liraglutide and telmisartan on the myofibroblast proliferation and Smad expression Relative to the sham control,the abundant α-SMA positive myofibroblasts were identified following 16 weeks of AAC,predominantly located in the outside of the blood vessels in the myocardium.However,the appearance of α-SMA positive myofibroblasts was inhibited by administration of liraglutide or telmisartan compared with the AAC group.Smad2 and Smad3 were barely phosphorylated in the sham control.However,at 16 weeks of AAC as analyzed by Western blot assay,the phosphorylation of Smad2/3 was markedly enhanced,consistent with increased total protein levels of Smad2/3.Furthermore,the total protein level of Smad4 was significantly upregulated,and total protein expression of Smad7 was downregulatedrelative to the sham group.However,all these changes in the protein expression of Smad family members induced by AAC were significantly reversed by administration of liraglutide or telmisartan.8.Effects of liraglutide and telmisartan on collagen synthesis and tissue fibrosis after AAC The protein levels of collagen I and ⅡI were significantly increased at AAC compared with the sham control.Administration of liraglutide or telmisartan was equally effective in reducing the production of collagen I and ⅡI after the rats.Consistent with upregulated expression of collagens I and ⅡI at 16 weeks of AAC,the region of deposited collagens as defined by percent collagen-rich areas was significantly expanded in the perivascular and interstitial myocardium.No newly-synthesized collagens were detected in the sham control throughout the experiment.The hearts treated with liraglutide or telmisartan showed a significant reduction in collagen deposition in both perivascular region and intermyocardium as defined by reduced collagen-rich area.9.Effects of liraglutide and telmisartan on cardiac performance after AAC Two-dimensional ultrasound system was used to detect the cardiac function after AAC and interventions.AAC caused a significant increase in the LVIDd relative to the sham group at 16 weeks of the experiment.Furthermore,cardiac systolic function as assessed by LVEF and LVFS was reduced by AAC relative to the sham group.Treatment with liraglutide or telmisartan enhanced cardiac performance compared with results in AAC group.Cardiac function was further analyzed by a BL-410 biological signal acquisition and processing system.At week 16,AAC significantly increased MAP,HR and LVEDP,and reduced LVSP relative to the sham control.Furthermore,+dp/dtmax and-dp/dtmax were significantly reduced.Treatment with liraglutide and telmisartan for 16 weeks effectively prevented the progression of cardiac dysfunction,consistent with the inhibition of cardiac hypertrophy and fibrosis.Conclusion: 1.Liraglutide treatment attenuates cardiac remodeling and improves heart function.2.The protection of liraglutide improves heart function may be associated with inhibiting AT1 R,the ratio of AT1R/ AT2 R and upregulation AT2 R,ACE2 and suppressing the production of reactive oxygen species.3.The protection of liraglutide improves heart function may be associated with an inhibition of TGF-β1/Smads signaling pathways and decrease of accumulate macrophages and proliferation of myofibroblasts.Part 2:Exogenous supplement of glucagon like peptide-1 protects the heart against pressure-overload induced myocardial fibrosis and dysfunction through inhibiting mTOR/p70S6 K signaling pathwaysObjective: Mammalian target of rapamycin(mTOR)and a ribosomal protein S6 kinase(p70S6K)mediate tissue fibrosis and negatively regulate autophagy.This study aims to investigate whether glucagon-like peptide-1(GLP-1)analog liraglutide protects the heart against aortic banding-induced cardiac fibrosis and dysfunction through inhibiting mTOR/p70S6 K signaling and promoting autophagy activity.Methods: 1.Experimental group: Male SD rats were observed for 16 weeks after abdominal aortic constriction(AAC)surgery(n=6 in each group).1)Sham control: rats underwent the same surgical procedure without banding the aorta;2)AAC: rats were produced abdominal aortic constriction(AAC)surge for 16 weeks;3)liraglutide treatment: rats were received a subcutaneous injection of liraglutide at a dose of 0.3 mg/kg twice daily after AAC;4)rapamycin treatment: rats were administered rapamycin via gastric gavage at a dose of 0.2 mg/kg/day after AAC.2.Measurement of the blood glucose and plasma GLP-1 levels using an ELISA kit.3.At the end of the experiment,the rat heart was rapidly removed and calculated the heart/body weight index(HW/BW).The MSA of cardiomyocytes was measured after conventional HE staining.4.Immunohistochemical staining for myofibroblasts.5.Detection of tissue fibrosis by Masson’s trichrome staining.6.Expression of GLP-1R,p-mTOR,mTOR,p-p70S6 K,p70S6K,LC3,Beclin-1,p62,collagen I and collagen Ⅲ by Western blot assay.7.Noninvasive evaluation of global cardiac function.8.Invasive hemodynamic measurements.Results: 1.Effects of liraglutide and rapamycin on basic state after AAC There was a trend in increase of blood glucose and body weight,but no statistical difference among four experimental groups.2.Effects of liraglutide and rapamycin on cardiac structural and HW/BW ratio after AAC Relative to the Sham control,AAC for 16 weeks significantly increased the weight of the heart and caused a structural dilation,which was significantly improved by liraglutide and rapamycin.HW/BW ratio increased significantly relative to the Sham group(4.07±0.22 vs.2.68 ±0.21,p<0.05).Treatment with liraglutide or rapamycin significantly reduced HW/BW ratio(2.98±0.20 and 2.85±0.18 vs.AAC group,all p<0.05).Relative to the Sham group,the MSA in the AAC group increased significantly(553±23 vs.232±25μm2,p<0.05).Treatment with liraglutide or rapamycin comparatively reduced the MSA to 294 ±24 μm2 or 322±23 μm2,all p<0.05 vs.AAC group.3.Effects of liraglutide and rapamycin on level of plasma GLP-1 and expression of GLP-1 receptor AAC caused a significant reduction in the level of plasma GLP-1(0.10±0.01 vs.0.15±0.01ng/ml,p<0.05)and the expression of GLP-1 receptor 26.1±5.6% compared with the Sham group.Relative to the AAC group,the level of plasma GLP-1 was significantly increased with administration of liraglutide or rapamycin(0.15±0.01 and 0.14±0.01ng/ml vs.AAC group,all p<0.05),respectively,consistent with an increase in expression of GLP-1 receptor in these groups.4.Effects of liraglutide and rapamycin on proliferation of myofibroblasts after AAC Relative to the Sham control,the abundant α-SMA positive myofibroblasts were identified by immunohistochemical staining following 16 weeks of AAC,predominantly located in the intermyocardium.However,the appearance of α-SMA positive myofibroblasts at this point was inhibited by administration of liraglutide or rapamycin compared with the AAC group.5.Effects of liraglutide and rapamycin on the expression of mTOR,p-mTOR,p70S6 K,p-p70S6 K after AAC AAC did not alter total protein level of mTOR and p70S6 K,but dramatically enhanced the level of phosphorylated mTOR and phosphorylated p70S6 K relative to the Sham control.Administration of liraglutide or rapamycin did not affect the total protein levels of mTOR and p70S6 K,but provided a compatible inhibition in the phosphorylation of both proteins(p-mTOR and p-p70S6K).6.Effects of liraglutide and rapamycin on the expression of LC3,Beclin-1 and p62 after AAC The densitometric analysis of LC3-I showed a steady increase after AAC relative to the Sham control(p<0.05),as evidenced by a decreased LC3-Ⅱ/LC3-I ratio.The expression of Beclin-1 was decreased by AAC when compared with rats in the Sham group.The protein level of p62 was constitutively expressed in the Sham control,but was significantly increased after AAC compared with rats in the Sham group(p< 0.05).With liraglutide treatment showed a compatible modulation in the phosphorylation of mTOR/p70S6 k,and the expression of LC3,Beclin-1 and p62 with rapamycin.7.Effects of liraglutide and rapamycin on synthesis of collagens and tissue fibrosis after AAC The densitometric analysis showed a statistically significant increase in the protein levels of collagen I and ⅡI after 16 weeks of AAC relative to the Sham control(all p<0.05).The percent collagen-rich areas in the interstitial myocardium and perivascular region were significantly expanded relative to the Sham control.No newly synthesized collagens were detected in the Sham control throughout the experiment.Treatment with liraglutide or rapamycin during the period of aortic constriction equivalently inhibited the expression of collagen I/ⅡI,and reduced the fibrotic deposition in both interstitial myocardium and perivascular region.8.Effects of liraglutide and rapamycin on cardiac global function after AAC Relative to the Sham control,16 weeks post-AAC significantly increased LVSs,LVIDd,LVIDs,LVPWd and reduced EF,FS.Treatment with liraglutide or rapamycin enhanced cardiac performance compared with results in AAC group.9.Effects of liraglutide and rapamycin on systolic and diastolic function after AAC AAC increased in HR and MAP,reduced LVSP,+dp/dtmax and-dp/dtmax increased LVEDP.Preservation of liraglutide or rapamycin for 16 weeks effectively prevented the progression of cardiac dysfunction.Conclusion: 1.The protection of liraglutide improves heart function may be associated with upregulation plsma GLP-1 and GLP-1R.2.The protection of liraglutide improves heart function are potentially mediated by enhancing autophagy activity via inhibiting mTOR/p70S6 K signaling pathways and decrease of accumulate macrophages and proliferation of myofibroblasts.Part 3: Inhibition and mechanism of glucagon-like peptide 1 on angiotensinⅡ-induced H9C2 cardiomyocyte hypertrophy and fibrosisObjective: It was selected for the the research with H9C2 cardiomyocytes induced by AngⅡ.The effects of liraglutide on the hypertrophy and fibrosis of H9C2 cells induced by AngⅡwere observed.It was further confirmed that the inhibition effect of liraglutide on cardiomyocyte hypertrophy and fibrosis via blocking the activation of AT1 R signaling,with angiotensinⅡreceptor antagonist telmisartan as a control.It was further confirmed that liraglutide can inhibit myocardial hypertrophy and fibrosis formation via inhibiting the mTOR/p70S6 K pathway,with Rapamycin and MHY1485 as a control,which are specific inhibition and stimulant of mTOR.Methods: 1.The H9C2 cardiomyocyte model induced by AngⅡ.2.Experimental group:(n=3 in each group)First part: 1)Control: with equal volume of medium;2)AngⅡ: treatment with 10-6mol/L AngⅡ;3)AngⅡ+Lira: treatment with 10-6mol/L AngⅡand 10-7mol/L liraglutide;4)AngⅡ+Telmi: treatment with 10-6mol/L AngⅡand 10-5mol/L telmisartan.Second part: 1)Control: with equal volume of medium;2)AngⅡ: treatment with 10-6mol/L AngⅡ;3)AngⅡ+Lira: treatment with 10-6mol/L AngⅡand 10-7mol/L liraglutide;4)AngⅡ+Rapa: treatment with 10-6mol/L AngⅡand 10-6mol/L rapamycin;5)AngⅡ+MHY1485: treatment with 10-6mol/L AngⅡand 10-5mol/L MHY1485;6)AngⅡ+Lira+Rapa: treatment with 10-6mol/L AngⅡ,10-7mol/L liraglutide and 10-6mol/L rapamycin;7)AngⅡ+Lira+ MHY1485: treatment with 10-6mol/L AngⅡ,10-7mol/L liraglutide and 10-5mol/L MHY1485;3.Detection of ANP and BNP in H9C2 cardiomyocytes by real-time fluorescence quantitative PCR(RT-PCR).4.TRITCPhalloidin stained for the area of cardiomyocytes.5.Expression of AT1 R,AT2R,p-mTOR,mTOR,p-p70S6 K,p70S6K,TGF-β1,and collagen I by Western blot assay.6.Detection of ROS levels in cardiomyocytes by flow cytometry.7.Immunofluorescence staining for TGF-β1、α-SMA and collagen I.Results: 1.The H9C2 cardiomyocyte model induced by AngⅡ After 10-6 mol/L AngⅡ was applied to cardiomyocytes for 24 hours,both the proliferation rate and the cell surface area were relatively maximum.Therefore,according to the experimental results,10-6mol/L AngⅡ was selected with 24 hours for subsequent experiments.2.Effect of different concentrations of liraglutide on H9C2 myocardial cell proliferation induced by AngⅡ 10-7 mol / L liraglutide was selected in the experiment of reducing the proliferation rate of H9C2 cardiomyocytes induced by AngⅡ.3.Effects of liraglutide and telmisartan on cardiomyocyte hypertrophy Cell surface area were measured with phalloidin.The results showed that the cell surface area in the Control group were 811.8 ± 64.1μm2,while 1191.8 ± 69.1 μm2 in the Ang Ⅱ group.After adding liraglutide and telmisartan,the areas were reduced to 1007.8 ± 62.3 μm2 and 902.3 ± 64.3 μm2,respectively(p<0.05).The contents of ANP and BNP in cardiomyocytes can reflect the degree of cardiomyocyte hypertrophy.Both liraglutide and telmisartan can reduce the m RNA content of cardiomyocytes ANP and BNP in AngⅡgroup.4.Effects of liraglutide and telmisartan on the expression of AT1 R and AT2 R in cardiomyocytes The expression of AngⅡreceptor was detected by Western blot.In AngⅡgroup,AT1 R expression increased and AT2 R decreased.After administration with liraglutide and telmisartan respectively,the expressions of AT1 R and AT2 R showed opposite expression levels compared with AngⅡgroup.5.Effects of liraglutide and telmisartan on the expression of ROS in cardiomyocytes The results showed that the ROS fluorescence brighter in the AngⅡgroup than in the Control group under the microscope.The ROS fluorescence with liraglutide and telmisartan treament was decreased.Consistent with those results under the microscope,the flow cytometry results showed that the FITC of ROS in the Ang Ⅱ group was 5546±202,which was significantly higher than the control group(3264±205)(p<0.05).After adding liraglutide and telmisartan,the FITC of ROS decreased to 4804 ± 203 and 3781 ± 218.6.Effects of liraglutide and telmisartan on TGF-β1 levels in myocardial cells The AOD of TGF-β1 in AngⅡgroup was 0.08±0.007,which was significantly higher than control group cells about 0.02 ± 0.008.With liraglutide and telmisartan,the AOD of TGF-β1 was 0.05±0.010 and 0.03±0.011.It was significantly reduced compared with the AngⅡgroup.It was further confirmed the trend of TGF-β1 expression by Western blot,which was insistent with the fluorescence results.7.Effects of liraglutide and telmisartan on the levels of α-SMA in myocardial cells Immunofluorescence results showed that α-SMA expression in cardiomyocytes was mainly located in the stromal of cardiomyocytes.The results showed that the AOD of α-SMA in AngⅡ group was significantly increased(0.11 ± 0.01 vs.0.05 ± 0.01 Control,p<0.05).After the administration of liraglutide or telmisartan drugs,the AOD of α-SMA expression in myocardial cells were 0.08 ± 0.01 and 0.06 ± 0.01,which were reduced compared to the AngⅡgroup.8.Effects of liraglutide and rapamycin on cardiomyocyte area The surface area of myocardial cells measured with phalloidin.In this group of experiments,the addition of rapamycin with AngⅡsignificantly reduced the increase in the surface area of myocardial cells.Liraglutide and rapamycin further reduced the cell surface area.Conversely,after adding MHY1485(mTOR-specific stimulant),the surface area of myocardial hypertrophy caused by Ang Ⅱ was increased to 1318.0 ± 80.1μm2.After adding liraglutide with MHY1485,the degree of myocardial hypertrophy by AngⅡwas reduced.9.Effects of liraglutide and rapamycin on the expression of mTOR and p70S6 K protein in cardiomyocytes Compared with the Control group,the AngⅡgroup did not change the total protein level of mTOR,but significantly increased the level of phosphorylated mTOR(phosphorylation at Ser2448).In addition,the total protein level of p70S6 K in cardiomyocytes did not change after Ang Ⅱ stimulation,but significant phosphorylated p70S6K(phosphorylated at Thr389)was detected(p<0.05).The administration of liraglutide or rapamycin does not affect the total protein levels of mTOR and p70S6 K,but has a consistent inhibitory effect on the phosphorylation of both proteins(p-mTOR and p-p70S6K).This phenomenon was aggravated combination of liraglutide or rapamycin.However,after adding MHY1485 with liraglutide after AngⅡ,the results of MHY1485 can be reversed and the phosphorylation levels of mTOR and p70S6 K can be reduced(p<0.05,Figure 3-14).10.Effects of liraglutide and rapamycin on collagen I levels in cardiomyocytes The expression of collagen I increased in the Ang Ⅱ group compared to the control group.Immunofluorescence results showed that the AOD of collagen I was significantly increased in the AngⅡgroup.The addition of liraglutide or rapamycin with AngⅡ administration equivalently suppressed the expression of collagen I and reduced the AOD in the interstitial of myocardial cells.Reverse the expression level of collagen I in MHY1485 group.Conclusion: 1.The protection of liraglutide on cardiomyocyte hypertrophy may be associated with inhibiting AT1 R,upregulation AT2 R and uppressing the production of reactive oxygen species.2.The protection of liraglutide reduces the expression of fibroblasts may be associated with an inhibition of TGF-β1 and myofibroblasts.3.Liraglutide reduces cardiomyocyte hypertrophy and fibrosis by inhibiting mTOR/p70S6 K signaling pathways. |
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