Magnolol attenuates right ventricular hypertrophy and fibrosis in hypoxia-induced pulmonary arterial hypertensive rats through inhibition of the JAK2/STAT3 signaling pathway / 中国药理学与毒理学杂志

OBJECTIVE Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol is a com?pound isolated from Magnolia officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. METHODS ① Male SD rats (220 g) were randomly divided into 5 groups (n=10): the normoxia group, the hypoxia group, the hypoxia plus Magnolol (10 and 20 mg·kg-1·d-1) group, and the vehicle group. Rats in the normoxia group were kept in a normoxia environment for 4 weeks, while rats in the hypoxia group were kept in a hypoxic chamber (10％ O2). The rats in the hypoxia plus magnolol groups were administered with magnolol at 10 or 20 mg·kg-1 (ip) once a day for 4 weeks. At the end of 4 weeks, the heart function was assessed by Doppler echocardiography, and then the rats were anesthetized with sodium pentobarbital (30 mg·kg-1, ip). The RVSP was measured by the right heart catheterization method. The heart tissues were collected and dissected to calculate the index of RV remodeling (RV/LV+IVS, RV/tibial length, or RV/body weight). Part of the RV samples was fixed with 4％paraformaldehyde for morphological analysis, while other samples were frozen at-80℃for molecular studies (measurements of ANP, BNP,α-SMA, and col?lagen Ⅰ/Ⅲ mRNA expression as well as p-JAK2/JAK2 and p-STAT3/STAT3 protein levels). ② To evaluate the effect of magnolol on hypoxia-induced myocardial hypertrophy and fibrosis, H9c2 or cardiac fibroblasts were divided into 7 groups: the control group, cells were cultured under normal conditions; the hypoxia group, cells were cultured under hypoxic condition (3％ O2);the hypoxia plus magnolol 10 mg·kg-1 group, magnolol10μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus magnolol 30 mg·kg-1 group, magnolol 20μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus TG-101348 group, TG-101348 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus JSI-124 group, JSI-124 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;and the hypoxia plus vehicle group, an equal volume of vehicle (DMSO) was added to the culture medium before the hypoxia treatment. At the end of the experiments, the cells were collected for morphological and molecular analysis. RESULTS In vivo, male Sprang-Daley rats were exposed to 10％ O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of RV remodeling index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3;these changes were attenuated by treating rats with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3％ O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagenⅠ, collagenⅢandα-SMA). Administration of mag?nolol and TG-101348 or JSI-124 (JAK2 selective inhibitors) could prevent the process of myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. CONCLUSION Magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway.

Effects of Xiefei Lishui recipe on left ventricle remodeling in rats with heart failure / 西安交通大学学报(医学版)

ABSTRACT:Objective To investigate the effects of Xiefei Lishui recipe on left ventricle remodeling in rats with heart failure.Methods Heart failure rat model was induced by intraperitoneal injections of doxorubicin. Rats were randomly divided into sham operation group (sham group),model group,traditional Chinese medicine group (TCM group),captopril group,and digoxin group.Distilled water,TCM [22 g/(kg · d)],captopril [19 mg/(kg·d)],and digoxin [32μg/(kg·d)]were administered by gastrogavage in rats in different groups for 35 days,respectively.Indices of ventricle remodeling and cardiac function,plasma levels of B-type natriuretic peptide (BNP),rennin (REN),angiotensin Ⅱ(AngⅡ)and aldosterone (ALD)were measured.Cardiomyocyte apoptosis index and collagen volume fraction (CVF)were analyzed.We also assayed myocardial mRNA expressions of MMP-2/9 and TIMP-1/2,and their tissue inhibiting factors TIMP-1 and TIMP-2.Results Compared with those in sham group,in model group cardiac function was significantly decreased,which could be significantly increased by TCM or captopril or digoxin,indices of cardiac remodeling were significantly increased,which could be significantly decreased by TCM or captopril (P<0.01 or P<0.05).Plasma levels of BNP,REN,AngⅡ and ALD,cardiomyocyte apoptosis index and CVF in model group were significantly increased,could be significantly decreased by TCM or captopril (P<0.01 or P<0.05).Myocardial mRNA expressions of MMP-2,MMP-9,TIMP-1 and TIMP-2 in model group were significantly upregulated compared with those in sham group, which could be significantly downregulated by TCM (P<0.01 or P<0.05).Conclusion Xiefei Lishui recipe can attenuate left ventricle remodeling and improve cardiac function in rats with heart failure, which may be related to downregulating myocardial mRNA expressions of MMP-2 ,MMP-9 ,TIMP-1 and TIMP-2 in the left ventricle as well as inhibiting cardiomyocyte apoptosis and myocardial fibrosis.

Effects of Intracoronary Administration of Autologous Adipose Tissue-Derived Stem Cells on Acute Myocardial Infarction in a Porcine Model

PURPOSE: Adipose-derived stem cells (ADSCs) are known to be potentially effective in regeneration of damaged tissue. We aimed to assess the effectiveness of intracoronary administration of ADSCs in reducing the infarction area and improving function after acute transmural myocardial infarction (MI) in a porcine model. MATERIALS AND METHODS: ADSCs were obtained from each pig's abdominal subcutaneous fat tissue by simple liposuction. After 3 passages of 14-days culture, 2 million ADSCs were injected into the coronary artery 30 min after acute transmural MI. At baseline and 4 weeks after the ADSC injection, 99mTc methoxyisobutylisonitrile-single photon emission computed tomography (MIBISPECT) was performed to evaluate the left ventricular volume, left ventricular ejection fraction (LVEF; %), and perfusion defects as well as the myocardial salvage (%) and salvage index. At 4 weeks, each pig was sacrificed, and the heart was extracted and dissected. Gross and microscopic analyses with specific immunohistochemistry staining were then performed. RESULTS: Analysis showed improvement in the perfusion defect, but not in the LVEF in the ADSC group (n=14), compared with the control group (n=14) (perfusion defect, -13.0+/-10.0 vs. -2.6+/-12.0, p=0.019; LVEF, -8.0+/-15.4 vs. -15.9+/-14.8, p=0.181). There was a tendency of reducing left ventricular volume in ADSC group. The ADSCs identified by stromal cell-derived factor-1 (SDF-1) staining were well co-localized by von Willebrand factor and Troponin T staining. CONCLUSION: Intracoronary injection of cultured ADSCs improved myocardial perfusion in this porcine acute transmural MI model.

Effect of therapy time from myocardial infarction onset to percutaneous coronary intervention on matrix metalloproteinases level and left ventricular remodeling in patients with acute anterior wall myocardial infarction / 中华老年医学杂志

Objective To investigate the effect of time from myocardial infarction (MI) onset to percutaneous coronary intervention (PCI) on plasma matrix metalloproteinases (MMPs) level and left ventricle (LV) remodeling in patients with acute ST-segment elevation myocardial infarction of anterior wall,and the relationship between MMPs and left ventricular remodeling.Methods All patients with anterior wall STEMI undergoing PCI were divided into early PCI group (PCI within 18 h after MI onset) and delayed PCI group (PCI between 2 and 3 weeks after MI onset).Plasma MMP-2 and MMP-9 activities were assayed on admission,and at 2 days,1 week after admission.One-year follow-up was finished after PCI.Left ventricular end-diastolic volume (LVEDV),left ventricular end-systolic volume (LVESV) and left ventricle ejection fraction (LVEF) were measured by echocardiography at baseline and one year later to elucidate the effects of time from onset to PCI on LV remodeling and the relationship between MMP-2,-9 levels and LV remodeling.Results The MMP -9 activity at 2 days after myocardial infarction was lower in early PCI group than in delayed PCI group [(46±26)μg/L vs.(66±40) μg/L,P=0.000].The changes in LVEDV and LVESV (△LVEDV and △LVESV) were lower and the change in LVEF (△LVEF) was higher in early PCI group than in delayed PCI group [(10.9±6.2) ml vs.(15.0±6.0)ml,(-1.1±5.7) ml vs.(2.9±4.6) ml,(5.5 ±4.0) ％ vs.(3.8±3.4) ％,P=0.000,0.000 and 0.015].MMP-9 had positive correlations with △LVEDV and △LVESV,and a negative correlation with △LVEF at admission and after 1-year follow-up (r=0.32,0.36 and-0.29,respectively,P=0.000,0.000 and 0.001).Conclusions MMP-9 activity at admission is correlated with LV remodeling and LV function.Early PCI can reduce MMP-9 activity and improve LV remodeling after myocardial infarction.

Hyperbaric oxygen on left ventricular ejection fraction preserved by the influence of left ventricular remodeling in patients with heart failure / 实用医学杂志

Objective To study hyperbaric oxygen on left ventricular ejection fraction preserved by the influence of left ventricular remodeling in patients with heart failure. Methods A total of 110 patients with heart failure and normal ejection fraction were randomly allocated into the control group (n=55) and the HBO group (n=55). The control group were given the routine therapy, the HBO group were treated with hyperbaric oxygen on the basis of conventional drug. The application of color doppler ultrasound before and after treatment for 3 months left ventricular structure indicators. Results Left ventricular structure indicators were significantly decreased (LVDd、IVSD、LVPWD、LVMI)(P<0.01). Compared with the control group the difference was statistically significant (P<0.05). Follow-up of 3 months, The treatment group composite cardiovascular events was fewer than the control group and had significant difference (P<0.05). Conclusion Hyperbaric oxygen therapy can significantly improve left ventricular ejection fraction preserved by heart failure of left ventricular diastolic and systolic function and reverse left ventricular remodeling,And can reduce the happening of cardiovascular events.

The Inflammatory Response and Cardiac Repair After Myocardial Infarction

One of the most important therapeutic targets of current cardiology practice is to determine optimal strategies for the minimization of myocardial necrosis and optimization of cardiac repair following an acute myocardial infarction. Myocardial necrosis after acute myocardial infarction induces complement activation and free radical generation, triggering a cytokine cascade initiated by tumor necrosis factor-alpha (TNF-alpha) release. When reperfusion of the infarcted area is initiated, intense inflammation follows. Chemokines, cytokines and the complement system play an important role in recruiting neutrophils in the ischemic and reperfused myocardium. Cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. The recruited neutrophils have potent cytotoxic effects through the release of proteolytic enzymes, and they interact with adhesion molecules on cardiomyocytes. In spite of the potential injury, reperfusion enhances cardiac repair; this may be related to the inflammatory response. Monocyte chemoattractant protein (MCP)-1 is upregulated in reperfused myocardium and can induce monocyte recruitment in the infarcted area. Monocyte subsets play a role in phagocytosis of dead cardiomyocytes and in granulation tissue formation. In addition, the transforming growth factor (TGF)-beta plays a crucial role in cardiac repair by suppressing inflammation. Resolution of inflammatory infiltration, containment of inflammation and the reparative response affecting the infarcted area are essential for optimal infarct healing. Here, we review the current literature on the inflammatory response and cardiac repair after myocardial infarction.

Relationship between Left Ventricular Remodeling and Systolic Function Assessed by Left Ventricular Mid-wall Fractional Shortening / 中国康复理论与实践

@#Objective To investigate the correlation between left ventricular remodeling and systolic function by mid-wall fractional shortening(mFS).Methods 51 cases of hypertension and 47 cases of healthy volunteers were enrolled and systolic parameters were measured as ejection fraction(EF), fractional shortening(FS) and mFS. Acorrding to left ventricular remodeling parameteres inclulding LVMI and RWT, hypertension group was divided into four subgroups. The correlation among these parameters were analyzed.Results Thicker left ventricular wall and lower mFS in patient with hypertension compaired with those in controll (P<0.05). There were negative correlation between mFS and RWTr=-0.42, P<0.05) and positive correlation between mFS and LVMI r=-0.67, P<0.01).Conclusion mFS is a valuable parameter compared with traditional parameteres such as EF and FS. There is a linear association between parameteres of ventricular remodeling and systolic function assessed by mFS in early stage of hypertension.

Effects of Losartan on Expression of TNF-? in Myocardium in Renovascular Hypertensive Rats / 中华高血压杂志

Objective To investigate the effect of angiotensin Ⅱ-1 receptor antagonist losartan on expression of tumor necrosis factor-alpha (TNF-?) in the ventricular myocardium in the renovascular hypertension rats. Methods Renovascular hypertension model was obtained by clip left renal artery in Sprague-Dawley(SD) rats. After operation the rats were divided into 3 groups: sham group, two-kidney one clip (2K1C) group, and losartan treatment group(2K1C and losartan 20 mg/kg?d by drinking). Tail blood pressure was determined every week. Animals were euthanized after treatment with losartan for four weeks. Cardiac index(CI)was calculated by HW/BW, and TNF-? protein of ventricle myocardium was determined by ELISA and immunohistochemistry. Results Losartan significantly decreased blood pressure(P