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Objective To investigate the relationship between serum stem cell factor receptor(c-kit)and myocardial fibrosis,cardiac function and prognosis in patients with dilated cardiomyopathy(DCM)complicat-ed with heart failure.Methods A total of 77 patients with DCM complicated with heart failure who were trea-ted in 3201 Hospital from May 2020 to June 2022 were enrolled in the study as study group,and 70 DCM pa-tients without heart failure were enrolled as the control group.The levels of serum c-kit mRNA and three my-ocardial fibrosis markers[α-smooth muscle actin(α-SMA),collagen type Ⅰ and collagen type Ⅲ]were detec-ted in the two groups.Cardiac function parameters were obtained by echocardiography.The relationship be-tween serum c-kit mRNA level and myocardial fibrosis and cardiac function was analyzed.According to the oc-currence of major adverse cardiovascular events(MACE),the patients were divided into poor prognosis group and good prognosis group.Multivariate Logistic regression analysis was used to analyze the factors affecting the prognosis of DCM patients complicated with heart failure.Receiver operating characteristic(ROC)curve was used to analyze the efficacy of serum c-kit mRNA level in predicting the prognosis of DCM patients.Results The serum c-kit mRNA level in the study group was lower than that in the control group(P＜0.05).The levels of three myocardial fibrosis indicators in the study group were higher than those in the con-trol group(P＜0.05).The left ventricular ejection fraction(LVEF)in the study group was lower than that in the control group(P＜0.05),and the left ventricular end-diastolic volume(LVEDV)and left ventricular end-systolic volume(LVESV)in the study group were higher than those in the control group(P＜0.05).Pearson correlation analysis showed that serum c-kit mRNA level was positively correlated with LVEF(r=0.677,P＜0.05),while negatively correlated with α-SMA,collagen type Ⅰ,collagen type Ⅲ,LVEDV and LVESV(r=-0.725,-0.748,-0.744,-0.745,-0.662,P＜0.05).Multivariate Logistic regression analysis showed that serum c-kit mRNA level is an independent factor for the prognosis of DCM patients with heart failure.ROC curve analysis showed that serum c-kit mRNA level had a sensitivity of 82.80％,a specificity of 81.80％,and an area under the curve of 0.829(95％CI:0.745-0.912,P＜0.001)for evaluating the progno-sis of DCM patients complicated with heart failure.Conclusion The serum c-kit mRNA level is significantly decreased in patients with DCM complicated with heart failure,and the serum c-kit mRNA level is correlated with myocardial fibrosis and cardiac function.The detection of serum c-kit mRNA level has a high efficacy in evaluating the prognosis of patients with DCM complicated with heart failure.
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Objective To observe the effect of sirtuin 1(SIRT1)on rat myocardial fibrosis induced by pressure overload and the proliferation of cardiac fibroblasts induced by angiotensin Ⅱ(Ang Ⅱ),and to explore the molecular mechanisms.Methods The pressure overload-induced myocardial fibrosis was established by abdominal aorta constriction(AAC)procedure in vi-vo.After treatment with SIRT1 activator,the myocardial interstitial fibrosis and the collagen volume fraction were evaluated by Masson's trichrome staining.The protein expressions of TGF-β1/Smads were determined by immunohistochemical analy-sis.After in vitro intervention of Ang Ⅱ or Ang Ⅱ with SIRT1 activator,the fibroblasts proliferation was detected by MTT as-say.The mRNA and protein expressions of collagen Ⅰ/Ⅲ(Col1α1/3α1),SIRT1 and TGF-β1/Smads in myocardial tissue and fi-broblasts were evaluated by qRT-PCR and Western blotting.Results Compared with the sham operation group,myocardial in-terstitial fibrosis was significantly observed in the pressure overload model group,myocardial collagen volume fraction was in-creased,expressions of Col1α1/3α1 and TGF-β1/Smads were significantly increased,and SIRT1 expression was decreased.After the intervention of SRT1720,SIRT1 activator could improve the myocardial interstitial fibrosis induced by pressure overload,downregulate the expressions of Col1α1/3α1 and TGF-β1/Smads,and upregulate the expression of SIRT1.Meanwhile,correla-tion analysis showed that the protein expression of SIRT1 was negatively correlated with the expression of TGF-β1.In addition,SRT1720 also inhibited Ang Ⅱ-induced fibroblast proliferation and increased expression of Col1α1/3α1 and TGF-β1.Conclusion Activation of SIRT1 inhibits pressure overload-induced myocardial fibrosis and Ang Ⅱ-induced fibroblasts proliferation via regu-lation of the TGF-β1/Smads signaling pathway.
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BACKGROUND:Studies have shown that resveratrol can relieve exercise-induced fatigue and protect the heart,but its action mechanism needs further study. OBJECTIVE:To explore the protective effect and regulatory mechanism of resveratrol on ventricular remodeling in exercise-induced fatigue rats. METHODS:Totally 48 male Sprague-Dawley rats were randomly divided into four groups,with 12 rats in each group.Rats in the blank control group were fed conventionally.After one week of adaptive training,rats in the exercise-related fatigue group and exercise-related fatigue with resveratrol supplement group were trained by 6-week weight-bearing swimming(5%body mass lead block fixed in the tail,70%-80%maximal oxygen uptake intensity),6 days a week,60 minutes a day.Rats in the resveratrol supplement group and exercise-related fatigue with resveratrol supplement group were given resveratrol(50 mg/kg per day)by gavage one hour after exercise intervention.Blank control group and exercise-related fatigue group were given the same volume of 2%dimethyl sulfoxide,6 days a week,once a day for 6 weeks.The body mass and heart mass of the rats were measured 24 hours after the last intervention.Plasma creatine kinase isoenzyme,cardiac troponin 1,pyruvate dehydrogenase and uncoupling protein 1 levels in myocardial tissue were determined by ELISA.The mRNA expression levels of ventricular remodeling-related factor Foxp1,transforming growth factor β1 and endothelin 1 were detected by RT-PCR. RESULTS AND CONCLUSION:Compared with the blank control group,the body mass of rats decreased and the heart mass increased in the exercise-related fatigue group(P＜0.05).Compared with the exercise-related fatigue group,the body mass and heart mass of the rats reduced in the exercise-related fatigue with resveratrol supplement group(P＜0.05).Compared with the blank control group,the levels of creatine kinase isoenzyme,cardiac troponin 1 and uncoupling protein 1 increased(P＜0.01),and the level of pyruvate dehydrogenase decreased(P＜0.01)in the exercise-related fatigue group.Compared with the exercise-related fatigue group,the levels of creatine kinase isoenzyme,myocardial troponin 1 and uncoupling protein 1 decreased(P＜0.05),and the level of pyruvate dehydrogenase increased(P＜0.05)in the exercise-related fatigue with resveratrol supplement group.Compared with the blank control group,the expression of the Foxp1 gene decreased(P＜0.01),and the expression of transforming growth factor β1 and endothelin 1 gene increased(P＜0.01)in the myocardium of the exercise-related fatigue group.Compared with the exercise-related fatigue group,the expression of the Foxp1 gene in the myocardium of the exercise-related fatigue with resveratrol supplement group increased(P＜0.01),while the expression of the transforming growth factor β1 and endothelin 1 gene decreased(P＜0.05).It is suggested that exercise-induced fatigue can promote myocardial adaptability and cause compensatory hypertrophy.Resveratrol can improve myocardial injury and energy metabolism and delay ventricular energy remodeling in rats.This effect may be related to the regulation of Foxp1/transforming growth factor β1/endothelin 1 signaling pathway.
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BACKGROUND:N6-methyladenosine(m6A)is a hot research topic in the mechanism of pathological cardiac remodeling and plays an important role in the development of cardiovascular diseases. OBJECTIVE:To summarize the possible mechanism by which m6A modification in non-coding RNAs regulates the main processes of pathological cardiac remodeling,such as pathological cardiac hypertrophy,cardiomyocyte death,myocardial fibrosis and vascular remodeling. METHODS:"m6A,non-coding RNA,pathological cardiac hypertrophy,cardiomyocyte apoptosis,cardiomyocyte pyroptosis,cardiomyocyte ferroptosis,myocardial fibrosis,vascular remodeling"were used as search terms in Chinese and English.Relevant literature from CNKI,PubMed and Web of Science databases published from January 1974 to April 2023 was retrieved,and finally 86 eligible articles were reviewed. RESULTS AND CONCLUSION:m6A modification is a highly dynamic and reversible modification.Pathological cardiac remodeling mainly involves pathological cardiac hypertrophy,cardiomyocyte apoptosis,cardiomyocyte pyroptosis,cardiomyocyte ferroptosis,myocardial fibrosis and vascular remodeling.m6A-related enzymes can regulate pathological cardiac remodeling processes through various non-coding RNAs and different signaling pathways,which can be used as a new potential intervention for cardiovascular diseases.In pathological cardiac remodeling,research on the regulatory relationship between m6A modification and non-coding RNAs is still in its infancy.With the development of epigenetics,m6A modification in non-coding RNAs is expected to have a new development in the regulation of pathological cardiac remodeling.
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Objective To investigate the effects of Optimized New Shengmai Powder on myocardial fibrosis in rats with heart failure based on the β1-AR/cAMP/PKA/CREB signaling pathway.Methods Totally 50 SD rats were randomly divided into sham-operation group(10 rats)and operation group(40 rats).The left anterior descending coronary artery was ligated to establish a rat model of heart failure.The modeling rats were randomly divided into the model group,the captopril group,and TCM low-and high-dosage groups,with 8 rats in each group.The administration groups received relevant medicine for gavage for 4 weeks.LVEF and LVFS in rats were detected by echocardiography,and measurement of heart and lung mass and calculation of heart and lung organ coefficients were performed,myocardial fibrosis degree was observed by histopathology,serum NT-ProBNP and cAMP,Col Ⅰ,and Col Ⅲcontent in myocardial tissue were detected by ELISA,immunohistochemical was used to detect β1-AR,cAMP positive expression,and Western blot was used to detect the expression of β1-AR/cAMP/PKA/CREB signaling pathway related proteins.Results Compared with the sham-operation group,the LVEF and LVFS of the model group rats were significantly decreased(P<0.01),and the heart and lung organ coefficient significantly increased(P<0.01);the number of myocardial cells decreased,collagen volume fraction increased,and the proportion of type Ⅰ/Ⅲcollagen fibers increased(P<0.01),the contents of serum NT-ProBNP and myocardial tissue Col Ⅰ and Col Ⅲincreased significantly,while the cAMP content in myocardial tissue decreased significantly(P<0.01),the positive expressions of β1-AR and cAMP were significantly decreased(P<0.01),the expressions of β1-AR,AC1,cAMP,p-PKA,and p-CREB proteins were significantly decreased,while protein expressions of p-Smad2,Col Ⅰ,Col Ⅲ,and α-SMA significantly increased(P<0.05,P<0.01).Compared with the model group,the administration groups could increase LVEF and LVFS and decrease heart and lung organ coefficient to different degrees in rats;increase the number of myocardial cells,decrease collagen volume fraction and the proportion of type Ⅰ/Ⅲ collagen fibers,down-regulate serum NT-ProBNP and the content of Col Ⅰ and Col Ⅲ in myocardial tissue,up-regulate the content of cAMP,increase the positive expressions of β1-AR and cAMP in myocardial tissue,up-regulate β1-AR,AC1,cAMP,p-PKA,p-CREB protein expression,and inhibit p-Smad2,Col Ⅰ,Col Ⅲ,and α-SMA protein expression,in which the effects of the TCM high-dosage group and captopril group were more pronounced(P<0.01,P<0.05).Conclusion Optimized New Shengmai Powder can effectively reduce myocardial fibrosis in heart failure rats,improve myocardial hypertrophy and remodeling,and increase left ventricular contractility,and the mechanism may be related to the activation of the β1-AR/cAMP/PKA/CREB signaling pathway.
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Objectives:Primary cardiac involvement (SSc-PHI) in systemic sclerosis is an important prognostic factor. We aimed to characterize and identify subclinical SSc-PHI using cardiovascular MRI to determine whether disease severity and serum biomarkers are associated with subclinical SSc-PHI.Methods:A total of 26 patients with SSc who had no history of cardiovascular disease or pulmonary hypertension underwent 3 T-enhanced cardiovascular MRI. Measurements included native T 1, extracellular volume, advanced gadolinium enhancement, T 2 mapping, and left ventricular volume function. Troponin T and N telencephalic natriuretic peptide precursors were also determined. Results:LGE was observed in 13 of 26 patients (50.0%), suggesting focal fibrosis, and T 2 mapping was significantly higher in the dcSSc group than in the lcSSc group ( P=0.009). Left ventricular volume and function were within the normal range in all patients, but final systolic left ventricular volume was significantly higher in dcSSc than in lcSSc ( P=0.021). The modified Rodnan skin score (mRSS) was significantly higher in patients with LGE focal fibrosis ( P=0.019). Logistic regression analysis confirmed the association between mRSS and LGE ( OR=1.224, P=0.037). In multivariate analysis, T 2 mapping was negatively correlated with disease course, and was correlated with dcSSc and fingertip ulcer ( R2=0.711, P=0.018, P=0.013, P=0.030). Troponin T was correlated with T 2 mapping ( r=0.555, P=0.049). Conclusions:Subclinical SSc-PHI is characterized by diffuse and focal myocardial fibrosis, but preserves myocardial systolic function. Subclinical SSC-Phi is associated with TNT, SSc disease severity, and complex peripheral vascular disease. These data provide information for identifying individuals at risk of SSc-PHI.
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AIM To explore the effects of genistein on reducing myocardial fibrosis in diabetic rats and the possible mechanism.METHODS The rat models of type 2 diabetes mellitus(T2DM)established by high-fat diet feeding and intraperitoneal streptozotocin(STZ)injection were randomly divided into the model group,the metformin group(100 mg/kg)and the low-dose and high-dose genistein groups(50,100 mg/kg),in contrast to those of the normal group given normal diet,with 10 rats in each group.After 8 weeks gavage of the corresponding drugs,the rats had detections of their weight of the body and the heart,the heart function,levels of the cardiac indices,the biomarkers of serum creatine kinase isoenzyme(CK-MB),aspartate aminotransferase(AST)and lactate dehydrogenase(LDH)activities,the extent of myocardial fibrosis,myocardial mRNA and protein expressions of transforming growth factor-β1(TGF-β1)and Smad homologue 3(Smad 3),and the myocardial distribution and expressions of Collagen Ⅰ and Collagen Ⅲ.RESULTS Compared with the model group,the genistein groups shared increased body weight,stroke output(SV)and ejection fraction(EF)(P<0.01);decreased levels of cardiac indices,left ventricular internal diameter end systole(LVIDs),CK-MB,AST and LDH activities(P<0.05,P<0.01);decreased relative area and myocardial expressions of CollagenⅠand CollagenⅢ(P<0.05,P<0.01);and decreased myocardial expressions of TGF-β1 and Smad3 mRNA and protein(P<0.05,P<0.01).Additionally,the high-dose genistein group was observed with decreased level of left ventricular internal diameter end-diastole(LVIDd)(P<0.05).CONCLUSION Genistein can protect the hearts of T2DM rat models by reducing their myocardial fibrosis via TGF-β1/Smad3 signaling pathway.
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Objective To explore the mechanism of Nuanxinkang Powder(aka.NXK,composed of Ginseng Radix et Rhizoma Rubra and Ilex Pubescens Radix)on improving ventricular remodeling in post-infarction mice based on the"metabolic-inflammatory"network regulating macrophage polarization.Methods ①Thirty C57BL/6J male mice were randomly divided into three groups:sham-operation group,model group,and NXK group(1.65 g·kg-1),with 10 mice in each group;the mouse model of myocardial infarction was replicated using left anterior descending coronary artery ligation;and the drug was administered by gavage once a day for 4 consecutive weeks.Masson staining was used to detect collagen deposition in myocardial tissue;ultrasound was used to detect cardiac function in mice:left ventricular ejection fraction(LVEF),left ventricular anterior wall thickness at end-systole(LVAWS)and left ventricular anterior wall thickness at end-diastole(LVAWD);flow cytometry was used to detect distribution of cardiac macrophages in mice;qPCR was used to detect mRNA expressions of lactate dehydrogenase A(LDHA),carnitine palmitoyltransferase 1(CPT-1),glucose transport protein 4(GLUT4),isocitrate dehydrogenase(IDH),and succinate dehydrogenase(SDHa)in heart tissue.②NXK was given 1.15 g·kg-1 NXK suspension to rats by gavage twice a day for 5 consecutive days to prepare NXK-containing serum.Lipopolysaccharide(LPS)-induced RAW 264.7 cells were used to construct a pro-inflammatory macrophage model.The cells were grouped into the following groups:blank serum control group(medium containing 5%blank serum+5%fetal bovine serum),NXK drug-containing serum group(medium containing 5%NXK drug-containing serum+5%fetal bovine serum),lipopolysaccharide group(medium containing 5%blank serum+5%fetal bovine serum+200 μg·mL-1 lipopolysaccharide),NXK drug-containing serum+ lipopolysaccharide group(medium containing 5%NXK drug-containing serum+5%fetal bovine serum+200 μ g·mL-1 lipopolysaccharide),all the groups were intervened for 16 hours.Glycolysis stress test was used to detect the level of glycolysis in RAW 264.7 cells;qPCR was used to detect the mRNA expression of mitochondrial pyruvate carrier(MPC1)in RAW 264.7 cells;and MitoSox Red fluorescent staining was used to detect the level of oxidative stress damage in mitochondria of RAW 264.7 cells.Results ①Compared with the sham-operation group,the blue-stained area of cardiac collagen fibres in mice of the model group was significantly increased,accompanied by thinning of the ventricular wall and enlargement of the left ventricular cavity;cardiac function indexes,such as LVEF,LVAWS,LVAWD,etc.,were all significantly reduced(P＜0.01,P＜0.001);the mRNA expressions of LDHA and CPT-1 were significantly up-regulated in the cardiac tissues of mice(P＜0.05),and the mRNA expressions of GLUT4,IDH and SDHa were significantly down-regulated(P＜0.05,P＜0.01),and CD86 staining positive cell was significantly increased(P＜0.001).Compared with the model group,mice in the NXK group showed a significant decrease in cardiac collagen fiber deposition and an increase in the thickness of the ventricular wall;cardiac function indexes such as LVEF,LVAWS and LVAWD were significantly increased(P＜0.05,P＜0.01,P＜0.001);and the mRNA expressions of LDHA and CPT-1 in the cardiac tissues of the mice were significantly down-regulated(P＜0.01,P＜0.001),mRNA expressions of GLUT4,SDHa and IDH were significantly up-regulated(P＜0.01),and the number of CD86 positive cells was significantly reduced(P＜0.001).②Compared with the blank serum control group,the cytosolic glycolysis level and ROS level of macrophages in the NXK serum-containing group did not change significantly(P＞0.05),whereas the glycolysis level and ROS level of macrophages in the lipopolysaccharide group were significantly increased(P＜0.01),and the mRNA expression of MPC1 was significantly down-regulated(P＜0.001).Compared with the lipopolysaccharide group,the macrophage glycolysis level and ROS level were significantly reduced in the NXK serum-containing + lipopolysaccharide group(P＜0.05,P＜0.01),and mRNA expression of MPC1 was significantly up-regulated(P＜0.001).Conclusion NXK can reduce myocardial fibrosis and ventricular remodeling after myocardial infarction and improve cardiac function in mice,and its mechanism may be related to the down-regulation of mRNA expression of LDHA in cardiac tissues,the up-regulation of mRNA expression of GLUT4,the improvement of cardiac glucose uptake after myocardial infarction,the inhibition of pro-inflammatory macrophage glycolysis,the increase in the expressions of SDHa and IDH to alleviate the accumulation of succinate and citrate,and the reduction of reactive oxygen species(ROS)generation,thereby reducing pro-inflammatory macrophage hyperpolarisation.
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Objective To understand the research situation of animal model of chronic heart failure(CHF)based on visualization software and bibliometrics methods,and to explore the research hotspots of animal models of CHF and guide the design of animal experiments and scientific research.Methods Literature related to animal model of CHF included in Web of Science core collection from January 1,2001 to October 10,2022 were retrieved.After reading the full text and obtaining the final included literature,VOSviewer and CiteSpace software were used to analyze the contents of institutions,journals and co-cited journals,authors and co-cited authors,keywords.Results A total of 961 papers were included,and the number of published papers increased steadily.The United States and China are the main research countries.Johns Hopkins University and Harvard University are major research institutions.The most frequently published and cited journals are AM J PHYSIOL-HEART C and CIRCULATION,etc..Schultz Harold D and Sabbah Hani N are more influential in author selection."Myocardial infarction","cardiac hypertrophy",and"rat"are the most frequent keywords,10 clusters and 18 emergent words were formed.Conclusion The research in this field is numerous,high quality but scattered.Commonly used animal models are rodents and dogs.The main modeling methods are surgery and drugs.The main pathological mechanisms are mainly myocardial hypertrophy,oxidative stress,and myocardial fibrosis.
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Objective To evaluate the pharmacodynamics of astragaloside Ⅳ derivatives for chronic heart failure, screen the candidate compounds and preliminarily explore the mechanism of the candidate compound HHQ16 against heart failure. Methods Chronic heart failure was induced by left anterior descending artery ligation in C57BL/6 mice for 4 weeks, and the mice were divided into 4 groups, including sham group, model group, positive control captopril group, and astragaloside Ⅳ derivatives group. After continuous intragastric administration for four weeks, the cardiac function was detected by echocardiography, and the optimal astragaloside Ⅳ derivative HHQ16 was selected for the treatment of heart failure. The preliminary mechanism for HHQ16 was further explored. The size of heart was observed by gross morphology; pathological changes were observed by HE staining; collagen deposition in the myocardium was observed by Masson staining; protein levels of myocardial fibrosis indexes COL1, COL3, and αSMA were detected by immunohistochemical staining, and mRNA levels of myocardial fibrosis indexes COL1, COL3, αSMA, and TGF-β1 were determined by qPCR technique. Results All astragaloside Ⅳ derivatives significantly improved cardiac function with increasing LVEF and LVFS, of which HHQ16 was the optimal compound. Compared with the model group, the heart volume of HHQ16 group was significantly reduced; myocardial hypertrophy was reduced; collagen deposition in myocardial tissues was reduced; and myocardial fibrosis indexes, COL1, COL3, αSMA and TGF-β1 mRNA levels, as well as the protein levels of COL1, COL3 and αSMA were significantly reduced. Conclusion HHQ16 is an optimal astragaloside Ⅳ derivatives for the treatment of chronic heart failure in mice, which could improve cardiac function by improving myocardial remodeling, and inhibit myocardial hypertrophy and myocardial fibrosis.
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Myocardial fibrosis （MF） is a prevalent pathological process in a spectrum of cardiac conditions， including myocardial infarction， hypertensive heart disease， and dilated cardiomyopathy. It is marked by an overabundance of extracellular matrix deposition， diminished myocardial compliance， and impaired cardiac function， which can lead to arrhythmias and sudden cardiac death. The current therapeutic approach primarily aims to suppress the progression of fibrosis， yet the therapeutic outcomes are poor. The pathogenesis of MF involves multiple signaling pathways， including the transforming growth factor-beta （TGF-β）/Smads signaling pathway， nuclear factor-kappa B （NF-κB） signaling pathway， phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， and mitogen-activated protein kinase （MAPK） signaling pathway. Traditional Chinese medicine （TCM） boasts a rich history in the treatment of cardiovascular diseases， offering distinctive benefits such as minimal side effects and high safety， and it has demonstrated promising therapeutic effects in the treatment of MF. In recent years， research has turned its attention to the application of TCM in modulating the signaling pathways associated with MF. It has been demonstrated that TCM can modulate the MF-related signaling pathways to exert anti-inflammatory effects， regulate cellular autophagy， cell proliferation， and apoptosis， reduce myocardial oxidative stress and damage， and inhibit the activation of fibroblasts and collagen synthesis， thereby exhibiting the potential to mitigate or even reverse the progression of MF. Experimental research and clinical observations indicate that TCM formulas such as Yixin Futing decoction， Luhong prescription， Zhilong Huoxue Tongyu capsules， and Kangjian Yixin prescription can effectively ameliorate MF and enhance cardiac function through the multi-component regulation of multiple cellular pathways. Specific TCM constituents， including isoliquiritigenin and astragaloside， have been shown to inhibit the expression of TGF-β1， thereby disrupting the Smad signaling pathway. Compounds like glycyrrhizic acid and allicin can suppress the NF-κB signaling pathway and curtail collagen synthesis in myocardial cells， and forsythoside can activate the PI3K/Akt signaling pathway， contributing to its anti-fibrotic effects.
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ObjectiveTo investigate the effect of Gualou Xiebai Banxiatang on cardiac function and myocardial histopathological changes in rats with ischemic myocardial injury， and to observe the effect of myocardial microvascular density （MVD）， phosphatidylinositol 3-kinase （PI3K）， mammalian target of rapamycin （mTOR）， hypoxia-inducible factor-1 alpha （HIF-1α）， and vascular endothelial growth factor （VEGF） signaling pathways on myocardial microangiogenesis. MethodSeventy male SD rats were randomly selected， with six rats in the normal group. The remaining rats were fed a high-fat diet and injected with isoproterenol hydrochloride （ISO，80 mg·kg-1·d-1， 2 d） to induce a hyperlipidemia-based ischemic heart disease model. After successful modeling， the rats were randomly divided into the model group， high， medium， and low dose groups of Gualou Xiebai Banxiatang， and the metoprolol group. The high， medium， and low dose groups of Gualou Xiebai Banxiatang were given Gualou Xiebai Banxiatang at 10.42， 5.21， 2.61 g·kg-1·d-1， respectively， while the metoprolol group was given metoprolol at 2.6 mg·kg-1·d-1. Both the normal and model groups were given an equivalent volume of physiological saline for 28 days. After the intervention， relevant tests were conducted， and serum was collected to measure heart function-related indicators. Hematoxylin-eosin （HE） and Masson staining were performed on ventricular tissue to observe pathological changes under a light microscope. Immunohistochemistry （IHC） was used to detect the positive expression of platelet endothelial cell adhesion molecule （CD31）. Enzyme-linked immunosorbent assay （ELISA） was used to detect the expression of N-terminal pro-brain natriuretic peptide （NT-proBNP） and VEGF. Western blot was used to detect the protein expression levels of PI3K/mTOR/HIF-1α/VEGF. ResultCompared with the normal group， the model group showed significantly increased serum levels of LDH， CK， CK-MB， NT-proBNP， and VEGF （P<0.01）， significantly increased collagen volume fraction （CVF） （P<0.01）， significantly decreased MVD （P<0.01）， and elevated protein expression levels of PI3K， mTOR， HIF-1α， and VEGF （P<0.05， P<0.01）. Compared with the model group， the metoprolol group had significantly lower serum levels of LDH， CK， CK-MB， and NT-proBNP （P<0.01）， significantly higher VEGF levels （P<0.01）， significantly decreased CVF （P<0.01）， significantly increased MVD （P<0.01）， and significantly increased protein expression levels of PI3K， mTOR， and VEGF （P<0.01）， with no statistically significant change in HIF-1α protein expression. Compared with the model group， the high and medium dose groups of Gualou Xiebai Banxiatang had decreased serum levels of LDH， CK， CK-MB， and NT-proBNP （P<0.05， P<0.01）， increased VEGF levels （P<0.05， P<0.01）， significantly reduced CVF （P<0.01）， increased MVD （P<0.05， P<0.01）， and significantly increased protein levels of PI3K， mTOR， HIF-1α， and VEGF （P<0.01）. In the low dose group of Gualou Xiebai Banxiatang， compared with the model group， serum levels of LDH and NT-proBNP were decreased （P<0.05）， VEGF was increased （P<0.05）. Moreover， CVF was decreased （P<0.05）， and the protein expression levels of PI3K， mTOR， HIF-1α， and VEGF were significantly increased （P<0.01）. ConclusionGualou Xiebai Banxiatang can improve cardiac function， reduce myocardial pathological damage， enhance endothelial cell function， promote myocardial microvascular formation， and upregulate the expression of PI3K， mTOR， HIF-1α， and VEGF proteins in myocardial tissue in rats with ischemic myocardial injury.
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OBJECTIVE To study the improvement effects of arbutin on myocardial fibrosis （MF） model rats and its mechanism. METHODS The network pharmacology was used to predict the potential target of arbutin in improving MF and molecular docking was used to validated. Totally 50 SD rats were given isoprenaline subcutaneously （5 mg/kg， once a day， for 14 consecutive days） to induce the MF model. Modeled rats were randomly divided into model group， captopril group （9 mg/kg）， arbutin low-dose， medium-dose and high-dose groups （50， 100， 200 mg/kg）， with 10 rats in each group. Another 10 healthy rats were included as normal group. Each group was given the corresponding drugs， once a day， for 28 consecutive days. Twenty-four hours after the final administration， electrocardiograms and heart-related indexes [heart weight index （HWI）， left ventricular weight index （LVWI）] of rats were detected； the levels of creatine kinase （CK）， lactate dehydrogenase （LDH）， N-terminal pro-brain natriuretic peptide （NT-proBNP） and type Ⅰ collagen （Col Ⅰ） and Col Ⅲ were detected in myocardial tissue of rats； the pathological changes of myocardial tissue were observed， and protein and mRNA expressions of adenosine deaminase （ADA） and adenosine kinase （ADK） were detected in the myocardial tissue of rats. RESULTS The results of network pharmacology showed that the main targets of arbutin improving MF were ADA and ADK. The results of molecular docking showed that arbutin bind stably with ADA and ADK. The results of experimental verification showed that compared with model group， the amplitude of ST and T waves in electrocardiogram were improved in administration groups， and the symptoms of atrial flutter were alleviated； HWI （except for arbutin medium-dose group）， LVWI， the levels of CK， LDH， NT-proBNP， Col Ⅰ and Col Ⅲ in the myocardial tissue of rats were decreased significantly （P＜0.05）； the degree of myocardial fibrosis in rats decreased； protein and mRNA expressions of ADA and ADK in the myocardial tissue were significantly increased （P＜0.05）. CONCLUSIONS Arbutin can improve cardiac fibrosis and cardiac function of MF model rats， the mechanism of which may be associated with up-regulating protein and mRNA expressions of ADA and ADK，influencing the nucleotide metabolism and collagen generation. zhangminghao@hactcm.edu.cn
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Myocardial fibrosis （MF） is a common pathological manifestation of various heart diseases. Due to the non-renewable nature of myocardial cells， the occurrence of MF represents irreversible damage to the myocardium. Previous studies have suggested that fibroblast-mediated collagen deposition is the main mechanism of MF. Recent studies have found that there is an immune regulation mechanism in the heart itself， and macrophage activation/polarization plays an important role in MF. With the deepening of traditional Chinese medicine research， scholars have found that traditional Chinese medicine can interfere with MF by regulating the renin-angiotensin-aldosterone system （RAAS） system and the inflammatory process， repairing the extracellular matrix， managing oxidative stress， and maintaining the balance of autophagy. This process is closely related to the activation and M1/M2 polarization of macrophages. Throughout the MF process， macrophage activation is beneficial， but excessive activation will be harmful. In the early stage of MF， appropriate M1 macrophage polarization is conducive to activating immunity and removing harmful substances. In the middle and late stages of MF， appropriate M2 macrophage polarization is conducive to remodeling the damaged myocardium. If macrophage activation is excessive/insufficient， or the balance of M1/M2 macrophage polarization is broken， the effect changes from improvement to destruction. Traditional Chinese medicines that regulate the activation/polarization of macrophages have the effects of replenishing Qi and nourishing Yin， as well as regulating Qi and activating blood， but there are also some heat-clearing， dampness-drying， and detoxification products. Therefore， the occurrence of MF may be caused by Qi and Yin deficiency， damp heat accumulation， and Qi stagnation and blood stasis. By summarizing the biological processes involved in macrophage activation/polarization in MF， this paper expounded on the research progress of traditional Chinese medicine in regulating macrophage activation and M1/M2 polarization from different angles to improve MF， so as to provide a reference for the treatment of MF with traditional Chinese medicine.
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OBJECTIVE To explore the effects of alfentanil （ALF） on myocardial fibrosis in rats with acute myocardial infarction （AMI） by regulating sphingosine kinase 1 （SphK1）/sphingosine 1-phosphate （S1P） signaling pathway. METHODS Male SD rats were collected to construct AMI model by the ligation of anterior descending branch of left coronary artery. The successfully modeled rats were randomly divided into AMI model group （Model group）， ALF low-dose group （ALF-L group， 0.25 mg/kg ALF）， ALF high-dose group （ALF-H group， 0.5 mg/kg ALF）， high dose of ALF+SphK1 activator group （ALF-H+K6PC-5 group， 0.5 mg/kg ALF+1 μg/g K6PC-5）. At the same time， a sham operation group （Sham group） was set up to perform only chest opening/closing operations without ligating the anterior descending branch of left coronary artery， with 15 rats in each group. Rats in each drug group were intraperitoneally injected with the corresponding drug solution， once a day， for 4 consecutive weeks. Twelve hours after the last medication， cardiac function indicators [left ventricular systolic pressure （LVSP）， left ventricular ejection fraction （LVEF）， left ventricular systolic diameter （LVSD）， left ventricular fractional shortening （LVFS）] of rats were detected in each group； the condition of myocardial infarction， pathological changes in myocardial tissue， and degree of fibrosis were observed； serum levels of brain natriuretic peptide （BNP） and cardiac troponin Ⅰ （cTnⅠ） in rats were detected. The protein expressions of collagen Ⅰ ， collagen Ⅲ ， matrix metalloproteinase-2 （MMP-2）， SphK1 and S1P were alsodetected in the myocardial tissue of rats. RESULTS Compared with the Sham group， the arrangement of myocardial cells in the Model group was disordered， with a large number of inflammatory cells infiltrating. The levels of LVSP， LVFS and LVEF in the Model group were significantly reduced （P＜0.05）； LVSD level， myocardial infarction area， collagen volume fraction， serum levels of BNP and cTnⅠ， the protein expressions of collagen Ⅰ， collagen Ⅲ， MMP-2， SphK1 and S1P in myocardial tissue were significantly increased or enlarged （P＜0.05）. Compared with the Model group， the pathological changes and degree of fibrosis in the myocardial tissue of rats in each dose group of ALF were improved or relieved， while the quantitative indicators of rats in the ALF-H group were significantly improved and significantly better than those in ALF-L group （P＜0.05）. K6PC-5 could significantly reverse the improvement effect of high-dose ALF on the above quantitative indicators in rats （P＜0.05）. CONCLUSIONS ALF can reduce myocardial fibrosis and improve cardiac function in AMI rats， and the effect may be related to the inhibition of the SphK1/S1P signaling pathway.
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Objective To investigate the effect of Colchicine on the prognosis of acute myocardial infarction(MI)in rats.Methods A total of 40male Sprague Dawley rats were randomly divided into 4groups:Sham operation group,MI+BLS(blank solvent)group,MI+Colchicine treatment group(MI+col/i.g),and MI+Colchicine intramyocardial injection(MI+col/i.m)group,with 10 rats in each group.We euthanized the rats 28days after modeling,recorded the rats'body weight and death,collected echocardiography,detec-ted the levels of serum inflammatory factors,liver and kidney functions by enzyme-linked immunosorbent assay(ELISA),stained the cardiac tissue samples by Masson,and analyzed the degree of myocardial fibrosis under Optical microscope.Results The survival rate within 28days after MI was not significantly improved by Colchicine.Compared with the model group,both Colchicine intragastric adminis-tration and intramyocardial injection could significantly reduce the serum inflammatory factors(P＜0.05),inhibit the myocardial fibrosis,and improve the cardiac function of the rats after MI(P＜0.001).The liver and kidney functions were not damaged in the Colchicine and intramyocardial injection groups,and the intramyocardial injection group could effectively alleviate the weight loss induced by systemic ad-ministration(P＜0.001).Conclusion Colchicine is safe and feasible in the treatment of MI in rats,it can significantly improve the car-diac function of rats after MI,and intramyocardial injection can effectively and significantly increase the tolerance of colchicine.
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AIM:To investigate the effect of cellular Sloan-Kettering Institute(c-SKI)protein expression on myocardial fibrosis in mice treated with andrgrapholide(Andr).METHODS:Male C57 mice were randomly divided into control group,model group[isoprenaline(ISO)group]and ISO+Andr group,with 6 mice per group.The mice in ISO and ISO+Andr groups were subcutaneously injected with ISO,while those in control group were injected with normal sa-line.The mice in ISO+Andr group was intragastrically given Andr,while those in ISO and control groups were given nor-mal saline.The histopathological characteristics of the heart tissue were detected by HE and Masson staining after 8 weeks of administration.The expression levels of c-SKI and extracellular matrix(ECM)-related proteins were detected by immu-nohistochemistry or Western blot.The c-SKI mRNA level was detected by qPCR.Human cardiac fibroblasts(HCFBs)were treated with different concentrations of Andr for 48 h.The cell viability was detected by CCK-8 assay,and the c-SKI and ECM-related protein levels were detected by Western blot.The transdifferentiated cell model was treated with the lowest effective dose of Andr.The cell morphology was observed under a microscope,the levels of c-SKI and ECM-related pro-teins were assessed by Western blot,and the c-SKI mRNA level was detected by qPCR.The transforming growth factor-β1(TGF-β1)-treated HCFBs were treated with the combination of c-SKI knockdown and Andr.The cell viability was detected by CCK-8 assay,and the levels of c-SKI and ECM-related proteins were detected by Western blot.RESULTS:After the intervention of Andr,the myocardial fibers in mice were neatly arranged,the morphology of myocardial cells was basically normal,the cell membrane was intact,and the collagen volume fraction was significantly reduced(P＜0.01).The mRNA and protein levels of c-SKI were significantly up-regulated(P＜0.05 or P＜0.01),and the protein levels of fibronectin 1(FN1),α-smooth muscle actin(α-SMA),vimentin and collagen type I(Col I)were significantly down-regulated(P＜0.01).After 50 μmol/L Andr treatment for 48 h,the viability of HCFBs was significantly decreased(P＜0.01),the pro-tein levels of Col I,α-SMA,vimentin and FN1 were significantly down-regulated(P＜0.01),and c-SKI expression was significantly up-regulated(P＜0.01).Compared with PBS group,the number of the HCFBs in TGF-β1 group increased with flattened and irregular morphological change,and the FN1,α-SMA,Col I and vimentin levels were significantly in-creased(P＜0.01),while c-SKI expression was significantly decreased(P＜0.01).After Andr intervention,the induction effect of TGF-β1 on HCFBs was reversed.Knockdown of c-SKI combined with Andr treatment in HCFBs significantly down-regulated c-SKI expression(P＜0.01),significantly up-regulated FN1,α-SMA,vimentin and Col I levels(P＜0.05),and significantly increased the cell viability.CONCLUSION:Andrgrapholide may affect the TGF-β1 signaling pathway by regulating c-SKI expression,and inhibit the proliferation of myocardial fibroblasts and ECM deposition,thus inhibiting myocardial fibrosis.
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Aortic stenosis is a valve disease characterized by dynamic and continuous changes in structure and function of left ventricle.Left ventricular remodeling,which embodies pathological changes in myocardial cellular and ventricular geometry,is an important prognostic factor of patients with aortic stenosis.Aortic valve replacement is the only effective treatment for severe aortic stenosis.Current guideline recommendations for interventions are based on symptoms and left ventricular ejection fraction.With the improvements of modern imaging technology,different patterns of remodeling,including hypertrophy and fibrosis,could be identified now.Studies also explored the close association between left ventricular remodeling and function in the setting of aortic stenosis.In this review,we aim to elucidate the characteristic imaging features and potential mechanisms of left ventricular remodeling,and further,we highlight the clinical value of specific imaging features and clinical application of modern imaging methods in the evaluation,risk stratification,and intervention decision-making for patients with aortic stenosis.
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OBJECTIVE@#To study effects of Shenmai Injection on hypertensive heart failure and its mechanism for inhibiting myocardial fibrosis.@*METHODS@#Salt-sensitive (Dahl/SS) rats were fed with normal diet (0.3% NaCl) and the high-salt diet (8% NaCl) to observe the changes in blood pressure and heart function, as the control group and the model group. Salt-insensitive rats (SS-13BN) were fed with the high-salt diet (8% NaCl) as the negative control group. After modeling, the model rats were randomly divided into heart failure (HF) group, Shenmai Injection (SMI) group and pirfenidone (PFD) group by a random number table, with 6 rats in each group. They were given sterilized water, SMI and pirfenidone, respectively. Blood pressure, cardiac function, fibrosis and related molecular expression were detected by sphygmomanometer, echocardiogram, enzyme linked immunosorbent assay (ELISA), hematoxylin-eosin staining, Masson staining, immunofluorescence and qPCR analysis.@*RESULTS@#After high-salt feeding, compared with the control and negative control group, in the model group the blood pressure increased significantly, the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were significantly reduced, and the serum NT-proBNP concentration increased significantly (all P<0.05); furthermore, the arrangement of myocardial cells was disordered, the edema was severe, and the degree of myocardial fibrosis was also significantly increased (P<0.05); the protein and mRNA expressions of collagen type I (Col I) were up-regulated (P<0.05), and the mRNA expressions of transforming growth factor β 1 (TGF- β 1), Smad2 and Smad3 were significantly up-regulated (P<0.05). Compared with HF group, after intervention of Shenmai Injection, LVEF and LVFS increased, myocardial morphology was improved, collagen volume fraction decreased significantly (P<0.05), and the mRNA expressions of Col I, TGF- β 1, Smad2 and Smad3, as well as Col I protein expression, were all significantly down-regulated (all P<0.05).@*CONCLUSION@#Myocardial fibrosis is the main pathological manifestation of hypertensive heart failure, and Shenmai Injection could inhibit myocardial fibrosis and effectively improve heart failure by regulating TGF-β 1/Smad signaling pathway.
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Rats , Animaux , Débit systolique , Chlorure de sodium , Rats de lignée Dahl , Fonction ventriculaire gauche , Défaillance cardiaque , Facteur de croissance transformant bêta-1/métabolisme , Hypertension artérielle , Fibrose , ARN messagerRÉSUMÉ
OBJECTIVE@#To investigate the effect of electroacupuncture (EA) at Neiguan (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHRs), and to explore the contribution of interleukin-1 β (IL-1 β), insulin-like growth factor 1 (IGF-1), and transforming growth factor β 1 (TGF- β 1) to the effects.@*METHODS@#Nine 12-weeks-old Wistar Kyoto (WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6 once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type I (Col I), collagen type 1 (Col 1) and the levels of IGF-1, 1L-1 β, TGF- β 1, matrix metalloproteinase (MMP)-2 and MMP-9 were examined in myocardial tissure respectively.@*RESULTS@#After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col I and Col 1 in myocardium tissue (P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group (P<0.01). Meanwhile, the increased levels of IL-1 β, IGF-1, TGF-β 1 in serum or myocardial tissue of SHRs, diminished MMP 9 mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment (P<0.05 or P<0.01). Furthermore, the contents of IL-1 β, IGF-1, TGF-β 1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively (P<0.01).@*CONCLUSION@#EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1 β/IGF-1-TGF- β 1-MMP9 pathway.