Left Ventricular Weight Index Research Articles

ELABELA-APJ-Akt / YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats.

The aim of this study was to investigate the function and mechanisms of ELABELA (ELA) in the aerobic exercise-induced anti-apoptosis and angiogenesis of ischemic heart. The MI model of Sprague-Dawley rat was established by ligation of the left anterior descending coronary artery. MI rats underwent 5 weeks of Fc-ELA-21 subcutaneous injection and aerobic exercise training using a motorized rodent treadmill. Heart function was evaluated by hemodynamic measures. Cardiac pathological remodeling was evaluated by Masson's staining and the calculation of left ventricular weight index (LVWI). Cell proliferation, angiogenesis and YAP translocation were observed by immunofluorescence staining. Cell apoptosis was analyzed by TUNEL. Cells culture and treatment were used to elucidate the molecular mechanism of ELA. Protein expression was detected by Western blotting. Angiogenesis was observed by tubule formation test. One-way or two-way analysis of variance and Student's t test were used for statistical analysis. Aerobic exercise stimulated the endogenous ELA expression. Exercise and Fc-ELA-21 intervention significantly activated APJ-Akt-mTOR-P70S6K signaling pathway, kept more cardiomyocytes alive and increased angiogenesis, so as to inhibit the cardiac pathological remodeling and improved the heart function of MI rats. Fc-ELA-32 also had the cellular and functional cardioprotective activities in vivo. In vitro, ELA-14 peptide regulated the phosphorylation and nucleoplasmic translocation of YAP and activated the APJ-Akt signaling pathway, so as to increase the proliferation of H9C2 cells. Moreover, the anti-apoptosis and tubule formation of HUVECs were also enhanced by ELA-14, while inhibition of Akt activity weakened such effects. ELA is a potential therapeutic member that plays a key role through APJ-Akt / YAP signaling axis in aerobic exercise-induced cardioprotection of MI rats.

Clinical characteristics and management of hemodialysis patients with pre-dialysis hypertension: a multicenter observational study

Background Hypertension is a leading preventable risk factor for cardiovascular disease in hemodialysis patients. Pre-dialysis systolic blood pressure (SBP) more than 160 mmHg was thought to be associated with increased risk of cardiovascular events and all-cause mortality. The present study was performed to explore the clinical characteristics and management of hemodialysis patients with pre-dialysis SBP ≥ 160 mmHg. Methods A total of 1233 patients undergoing hemodialysis from nine hemodialysis centers were enrolled. Pre-dialysis and home BP were measured and clinical data were collected. The characteristics of patients with pre-dialysis SBP ≥ 160 mmHg were explored. Clinical parameters between hypertensive and non-hypertensive patients were compared. The partial correlation analyses performed to identify the associations between BP and clinical parameters. Results There were 24.6% of the hemodialysis patients had pre-dialysis SBP ≥ 160 mmHg and the average SBP was 173.8 ± 10.9 mmHg. Only 21.4% of the patients achieved dry weight after dialysis and up to 30.2% of patients were not given combination therapies of antihypertensive drugs. Compared to patients with pre-hemodialysis SBP < 160 mmHg, patients with pre-dialysis SBP ≥ 160 mmHg had lower target-reaching rate of Kt/v and higher incidences of intradialytic hypotension and muscle spasm. Most patients (96%) with pre-dialysis SBP ≥ 160 mmHg had home SBP≥ 135 mmHg. Patients with home SBP ≥ 160 mmHg had higher left ventricular weight index and lower hemoglobin levels when compared to their counterparts with home SBP <160 mmHg. Conclusions Pre-dialysis SBP ≥ 160 mmHg is common in clinical practice and most of the patients could diagnosed to be hypertensive according to their home SBP. Patients with pre-dialysis SBP ≥ 160 mmHg are more likely to be subjected to dialysis insufficiency and intradialytic complications. Achieving dry weight and sufficient pharmacologic interventions should be strengthened to improve BP control in the hemodialysis population.

A Heart Failure Model Established by Pressure Overload Caused by Abdominal Aortic Contraction in Rat.

Heart failure is a complex clinical syndrome in which ventricular filling or ejection capacity is impaired due to structural or functional diseases of the heart. In order to establish a stable heart failure model, we investigated cardiac parameters in rats with abdominal aortic contraction and normal rats, including the left ventricular posterior wall diameter (LVPWd), the interventricular septum thickness of end-diastolic (IVSd), the left ventricular end-diastolic diameter (LVEDd), the left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). Rats were randomly divided into experimental group (n = 20) and control group (n = 20). The experimental group underwent modified abdominal aortic constriction, while the control group only isolated the abdominal aorta without constriction. The results showed that the survival rate of rats in the experimental group was 85% after one week of operation, while the survival rate of rats in the control group was 100%. Five weeks after operation, the left ventricular posterior wall diameter (LVPWd) and the interventricular septum thickness of end-diastolic (IVSd) in the experimental group were all increased compared with those in the control group, and the differences were statistically significant (p < 0.05); the left ventricular end-diastolic diameter (LVEDd) in the experimental group showed an increasing trend compared with the control group, but p > 0.05; compared with the control group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the experimental group showed downward trend, but p > 0.05. 10 weeks after operation, the LVPWd, IVSd, and LVEDd of the experimental group were increased compared with the control group, p < 0.05, and the LVEF and LVFS of the experimental group were decreased compared with the control group, p < 0.05. Compared with the control group, the BNP of the experimental group increased significantly, p < 0.05. The heart weight index and left ventricular weight index of rats in the experimental group were significantly higher than those in the control group, p < 0.05. HE staining showed that the myocardial cells in the experimental group increased in volume, disordered cell arrangement, widened gaps, increased nuclear hyperchromia, and uneven staining. This paper provides a theoretical basis for the study of heart failure.

Injection of Matrix Metalloproteinase-9 Leads to Ventricular Remodeling.

Objective Previous studies have found that some ventricular remodeling is accompanied by increased matrix metalloproteinase-9 (MMP-9) in vivo, and MMP-9 inhibitors can reduce ventricular remodeling. However, there is still no direct evidence that MMP-9 causes ventricular remodeling. In this study, MMP-9 was injected into rats to observe whether MMP-9 caused ventricular remodeling, thereby providing direct evidence of MMP-9-induced ventricular remodeling. Methods Forty-eight eight-week-old male Wistar rats were randomly divided, by weight, into control, low-, medium-, and high-dose MMP-9 groups and were administered normal saline or recombinant rat MMP-9 0.7, 1.4, or 2.1 ng/g, respectively, via intraperitoneal injection, twice per week. On the 28th day, six rats were randomly selected from each group (Stage I). The remaining rats continued receiving injections until the 56th day (Stage II). Echocardiography was performed to observe cardiac structure and function, and the left ventricular mass index (LVWI) was calculated. Myocardial pathological changes and the collagen volume fraction (CVF) were observed by HE and VG staining in myocardial tissue. MMP-9 levels in serum were tested using ELISA. Myocardial MMP-9 levels were measured using Western blots, and the myocardial expression levels of MMP-9 mRNA were assessed using RT-PCR. Results During Stage I, serum MMP-9 and myocardial MMP-9 mRNA levels are increased; hypertrophic cardiomyocytes, disorderly arrangement of fibers, and endochylema dissolution are observed in the medium- and high-dose groups. The left ventricular weight index (LVWI) and myocardial MMP-9 increased, and the collagen volume fraction (CVF) reduced in the high-dose group. In Stage II, the left ventricular end-diastolic volume (LVEDV) and diameter (LVIDd) are higher, and CVF decreased in the medium- and high-dose groups. Myocardial pathological lesions intensified. Serum MMP-9 in the model groups and myocardial MMP-9 in the medium- and high-dose groups are increased. Conclusions Injection of MMP-9 can lead to ventricular remodeling.

Protective effect of sinomenine on isoproterenol-induced cardiac hypertrophy in mice.

To study the effect of sinomenine (Sin) on isoproterenol (Iso, β-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, β blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1β levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1β levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1β, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.

Compaired Sacubitril/Valsartan with Benalapril on the Left Ventricular Remordeling of Ami after PPCI: A case-control study

Background: To compare the effect of sacubitril/valsartan with benalapril on left ventricular remodeling in patients with acute myocardial infarction. Materials and Methods: 85 patients with acute ST segment elevation myocardial infarction who were treated with PCI in the Second Affiliated Hospital of Tianjin Medical University. The patients were randomly divided into two groups: the experimental group (sacubitril/valsartan, 25-100mg/d, BID) and the control group (benalapril, 5-10mg, QD). Color Doppler echocardiography was performed after 1 month and 3 months respectively, interventricular septal thickness, septal motion amplitude, left ventricular end diastolic diameter, left ventricular end systolic diameter, posterior wall thickness, posterior wall motion amplitude, LVEF, left ventricular weight, left ventricular weight index, NT Pro-BNP, gender, height, weight, body surface area were collected. In order to evaluate the influencing factors in the process of ventricular remodeling, binary multivariate logistic regression analysis was carried out for the indicators with statistical differences in the conclusions of the above control study. Subgroup analysis was carried out and the samples were divided into four subgroups according to gender,age, initial ejection fraction . Resulst: one month after the treatment of sacubitril/valsartan or benalapril, only the left ventricular end systolic diameter was statistically different between the two groups (P &lt; 0.05), and the other indexes were not statistically different. Three months after treatment with sacubitril/valsartan or benalapril, there were statistical differences in the indexes related to myocardial remodeling between the two groups (P &lt; 0.05). The results of multivariate logistic analysis showed that the index of left ventricular end systolic diameter was statistically significant (or=0.006, 95% CI: 0.733-0.981). Acute myocardial infarction whose LVEF is less than 50%, show sacubitril/valsartan is better than traditional ACEI. Conclusion: sacubitril/valsartan Compared with benalapril is better on left ventricular remodeling in patients with ST segment elevation acute myocardial infarction.

Investigation of effects of traditional Chinese medicine astragalus heart-protecting decoction on rats with dilated cardiomyopathy

To investigate the effect of astragalus heart-protecting decoction on rats with dilated cardiomyopathy (DCM). 36 healthy rats were divided into normal control group (n = 12, unmodeled rats without receiving decoction), DCM + control group (n = 12, modeled rats without decoction), and DCM + treatment group (n = 12, modeled rats receiving decoction). Outcomes of the three groups were compared. Serum brain natriuretic peptide and matrix metallopeptidase 10, ventricular remodeling indicators, whole heart weight index and left ventricular weight index were significantly lower in normal control group than in the DMC + treatment and DMC + control groups, so was that in DMC + treatment group compared with those in DMC + control group (P < 0.05). Additionally, the normal control group had higher superoxide dismutase level but lower malondialdehyde and lactate dehydrogenase levels than the DMC + treatment and DMC + control groups (P < 0.05). Regarding myocardial histology or myocardial fibrosis, the DMC + treatment group highlighted better performance than the DMC + control group, with differences from those in the normal control group though. Astragalus heart-protecting decoction has a positive effect in the treatment of rats with DCM.

Irbesartan ameliorates myocardial fibrosis in diabetic cardiomyopathy rats by inhibiting the TGF&amp;beta;1/Smad2/3 pathway

Myocardial fibrosis (MF) is an important pathological change in diabetic cardiomyopathy. The aim of the present study was to investigate whether irbesartan serves a role in improving MF in a diabetic rat model. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured in rats using biochemical methods. Heart weight index (HWI), left ventricular weight index (LVWI), left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were also measured, whilst type I collagen and hydroxyproline content in myocardial tissue was quantified. Western blotting was used to measure the expression of transforming growth factor β1 (TGFβ1), phosphorylated (p)-Smad2/3 and collagen type I α 1 chain (COL1A1) inmyocardial tissues or rat cardiac fibroblast (RCF) cells. Cell proliferation was measured using EdU staining. Procollagen type III N-terminal peptide (PIIINP) content, FBG, TC, TG and LDL-C levels were found to be significantly higher, whilst HDL-C levels were found to be significantly lower in rats in the diabetic group. Those in the diabetic group also exhibited significantly elevated HWI, LVWI, LVEDP, myocardial tissue type I collagen content and hydroxyproline content values, but significantly reduced LVSP. Changes in the aforementioned indicators were reversed after treatment with irbesartan, where the protein expression levels of TGFβ1 and p-Smad2/3 in myocardial tissue were also significantly reduced. In RCF cells, irbesartan significantly reversed high glucose-induced upregulation of TGFβ1 expression, Smad2/3 phosphorylation and COL1A1 expression, as well as reducing cell proliferation and rat type I PICP and PIIINP levels. Application of pirfenidone produced additive effects on reducing the expression levels of the proteins aforementioned when combined with irbesartan. Therefore, the present results demonstrated that irbesartan reduced the activity of the TGFβ1/Smad2/3 pathway and ameliorated diabetic MF by downregulating the expression of TGFβ1.

Atorvastatin improves the cardiac function of rats after acute myocardial infarction through ERK1/2 pathway.

To study the regulatory effect of atorvastatin (ATV) on the extracellular signal-regulated kinase (ERK) 1/2 pathway and explore its effect on acute myocardial infarction (AMI) rats. The rat model of AMI was established, and the model rats were randomly divided into AMI group and ATV-AMI group, and Sham group was also set up. At 4 weeks after successful modeling, the cardiac function indexes of Sprague-Dawley (SD) rats were detected via magnetic resonance imaging (MRI) and echocardiography (ECG). After the rats were executed, the left ventricular weight index (LVWI) was measured, and the myocardial damage was detected via hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Moreover, the messenger ribonucleic acid (mRNA) expressions of collagen I and collagen III in myocardial tissues were detected via Real Time-Polymerase Chain Reaction (PCR), and the expressions of ERK1/2 pathway-related proteins in myocardial tissues were detected via Western blotting. After administration of ATV for AMI, the fractional shortening (FS%) and ejection fraction (EF%) were significantly restored. Compared with that in ATV-AMI group, LVWI was significantly increased in AMI group (p<0.05), indicating that ATV could improve the cardiac function after AMI. The results of HE staining and TUNEL staining showed that ATV-AMI group had slighter myocardial damage and significantly lower apoptosis rate than AMI group, indicating that ATV could reverse AMI through the ERK1/2 pathway. Besides, the mRNA expressions of collagen I and collagen III were higher in AMI group and ATV-AMI group than those in Sham group (p<0.05), while they were significantly lower in ATV-AMI group than those in AMI group (p<0.05). The expressions of ERK1/2 pathway-related proteins were also higher in AMI group and ATV-AMI group than those in Sham group (p<0.05). ATV can significantly improve the cardiac function of SD rats after AMI, whose mechanism is related to the expression of the ERK1/2 pathway.

Effect of Irbesartan on AGEs-RAGE and MMPs systems in rat type 2 diabetes myocardial-fibrosis model.

There are about 425 million diabetes patients (20-79 years) in the world according to the International Diabetes Federation Diabetes Atlas - 8th Edition. The cardiovascular complication is one of the major causes of death in diabetes patients. Myocardial fibrosis is one of the serious pathological changes, so investigating the pathogenesis of myocardial fibrosis has the significant value. Our study aims to investigate the effect of Irbesartan (the angiotensin II receptor antagonist) on the changes of AGE-RAGE system and MMP family components, and analyzes the potential mechanisms in type 2 diabetes-induced myocardial fibrosis. Our results provide the theoretical base for better understanding the pathogenesis in type 2 diabetes-induced myocardial complication. It is useful for clinicians to select the effective therapeutic measures for treatment of type 2 diabetes-induced organ fibrosis.

Linggui Zhugan Decoction (苓桂术甘汤) Inhibits Ventricular Remodeling after Acute Myocardial Infarction in Rats by Suppressing TGF-β1/Smad Signaling Pathway

To investigate the inhibitory effect of Linggui Zhugan Decoction (LZD, ) on the ventricular remodeling (VR) after acute myocardial infarction (AMI) and related mRNA and proteins expression in transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway, and explain its putative mechanism. A VR model was generated by ligation of coronary artery in mice. Two weeks after surgery, 60 mice were randomly divided into the model group, the sham-operation group (distilled water), the positive control group (2.4 mg/kg simvastatin), and the low-, medium- and high-dose LZD groups (2.1, 4.2, 8.4 g crude drug/kg, respectively) by a random number table, 10 mice in each group. Mice in each group was treated for 4 weeks. Changes of hemodynamics indices and cardiac weight index were detected by the PowerLab data acquisition and analysis recording instrument. Morphology changes of myocardial tissue were observed by hematoxylin-eosin and Masson staining. The expressions of TGF-β1, Smad2, Smad3, p-Smad2 and p-Smad3 in myocardial tissue were detected by Western blotting. The mRNA expressions of TGF-β1, Smad2 and Smad3 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expressions of matrix metalloprotein 2 (MMP2), MMP9, collagen I and collagen III were observed by immunohistochemical methods. VR mice showed significant dysfunction in hemodynamic indices and cardiac structure and function. Compared with the shamoperation group, myocardial tissue damage, interstitial fibrosis occurred in the model mice, left ventricular systolic pressure (LVSP), left ventricular pressure maximum contraction rate (+dp/dtmax) and left ventricular pressure maximum relaxation rate (-dp/dtmax) decreased significantly (all P<0.01), while left ventricular end-diastolic pressure (LVEDP), cardiac weight index and left ventricular weight index elevated significantly, meanwhile TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I, collagen III protein expressions in myocardial tissue and TGF-β1, Smad2 and Smad3 mRNA expressions increased significantly (all P<0.01). Compared with the model group, LZD could significantly improve the pathological changes of myocardial tissue, increase LVSP, +dp/dtmax and -dp/dtmax, lower LVEDP, reduce the whole heart weight index and left ventricular weight index and inhibit the over-expressions of TGF-β1, p-Smad2, p-Smad3, Smad2, Smad3, MMP2, MMP9, collagen I and collagen III proteins in myocardial tissue and mRNA expressions of TGF-β1, Smad2 and Smad3 (P<0.05 or P<0.01). LZD can significantly suppress VR induced by AMI, and its underlying mechanism may be associated with its inhibitory effect on the TGF-β1/Smad signaling pathway.

Effects of Atractylodes macrocephala rhizoma on isoproterenol-induced myocardial hypertrophy in mice

Background: The studies about the protective effect on the heart of single Atractylodes macrocephala rhizoma (AMR) herb and mechanisms have not been reported. Objective: The purpose of this study was to assess the effects of AMR on attenuating myocardial hypertrophy induced by isoproterenol (ISO) in mice. Materials and Methods: Mice were randomly divided into normal control group, ISO control group, ISO plus metoprolol (60 mg/kg) group, ISO plus AMR (2, 4, and 8 g/kg) groups, and AMR (4 g/kg) control group. The mice with myocardial hypertrophy were established by subcutaneous (s.c.) injection with ISO (2 mg/kg/d) and administered intragastrically with the corresponding drugs in the volume of 0.2 mL/10 g/d for 7 days. In the normal and AMR control groups, mice were injected (s.c.) with physiological saline (the solvent for ISO) and administered intragastrically with drinking water for 7 days. Results: Compared with the ISO-induced group, AMR significantly decreased heart weight index, left ventricular weight index, and average transverse area of cardiomyocytes, significantly increased the activity of total superoxide dismutase in serum and the level of the angiotensin II receptor type (AT) gene expression in myocardium and significantly decreased the contents of malondialdehyde, cyclic adenosine monophosphate , and aldosterone in serum and angiotensin II (Ang II) in myocardium. Conclusion: The ability of AMR to mitigate myocardial hypertrophy is partly associated with its anti-oxidative effect, restraining excessive secretion or activation of neuroendocrine factors, and the stronger upward effect on AT2gene expression than AT1.

Cardioprotective effect of erythropoietin in rats with acute myocardial infarction through JNK pathway.

To explore the molecular mechanism of the cardioprotective effect of erythropoietin (EPO) in the rats with acute myocardial infarction (AMI) via the c-Jun N-terminal kinase (JNK) pathway. The rat AMI models were constructed and randomly divided into the EPO group, AMI group, and Sham group. At 2 weeks after successful modeling, the cardiac function-related indicators of rats were determined, and after the rats were sacrificed, the left ventricular weight (LVW) index was measured. The enzyme-linked immunosorbent assay (ELISA) and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were employed to determine the levels of the related serum inflammatory factors and myocardial apoptosis, respectively. The apoptosis and the expression levels of the JNK pathway-related messenger ribonucleic acids (mRNA) and proteins in the myocardial tissues of all groups of rats were determined via Real Time-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry. After intervention with EPO, the EPO group had a substantially lower left ventricular end-diastolic pressure, but a remarkably higher left ventricular systolic pressure than the AMI group (p<0.05), and the LVW and LVW/body weight (BW) notably declined in the EPO group compared with those in AMI group (p<0.05). According to the ELISA results, the inflammatory factors were substantially raised in the AMI group compared with those in the other two groups (p<0.05) and significantly lowered after treatment with EPO (p<0.05). The TUNEL assay results revealed that EPO treatment could reverse the pathological changes in AMI to decrease the apoptosis to a large extent. It was detected via RT-PCR and immunohistochemistry that, compared with those in the Sham group, the expression level of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) was substantially decreased, but the expression levels of pro-apoptosis gene Bcl-2 associated X protein (Bax) and the JNK pathway-related JNK and c-Jun were evidently elevated in the AMI group (p<0.05). Moreover, the expression level of Bcl-2 was remarkably raised (p<0.05) and the expression levels of Bax, JNK, and c-Jun remarkably declined (p<0.05) in the EPO group after intervention with EPO. EPO can inhibit the inflammatory responses and decrease the myocardial apoptosis to protect the heart of the AMI rats, and its mechanism of action is related to the inhibition of the expression of the JNK pathway.

Effect of fermented Cordycepssinensis on doxorubicin‑induced cardiotoxicity in rats.

Cordyceps sinensis (CS) is a prominent medicinal herb in traditional Chinese medicine, and fermented CS is frequently used as a substitute for natural CS. Doxorubicin (DOX), an antitumor drug used in chemotherapy, is limited by its poor cardiotoxicity. The aim of the present study was to evaluate the protective effect of fermented CS against DOX-induced cardiotoxicity and the potential underlying mechanisms. Male Sprague-Dawley rats (180–200 g) were randomly assigned to seven different treatment groups: Normal control, DOX control, DOX+captopril (0.05 g/kg), 0.75, 1.5 and 3 g/kg DOX+CS, and the CS (1.5 g/kg) control. Histopathological changes, cardiac energy metabolism, cyclic adenosine monophosphate (cAMP) signaling and the associated mRNA expression of AMP-activated protein kinase (AMPK) were then evaluated. Fermented CS decreased the left ventricular weight index, heart weight index and mortality; however, it increased diastolic blood pressure and mean arterial pressure. In addition, it shortened the duration of the QRS complex and Sα-T segment, decreased serum creatine kinase (CK) and aspartate aminotransferase activity, inhibited histopathological changes and reduced brain natriuretic peptide content. Treatment with fermented CS also increased the activities of superoxide dismutase and glutathione peroxidase, reduced malondialdehyde content, increased the mitochondrial activities of Na+K+-adenosine 5′-triphosphate (ATP) ase, Ca2+Mg2+-ATPase and CK, and increased the creatine phosphate/ATP ratio and AMP/ATP ratio. Furthermore, it decreased the ATP/adenosine 5′-diphosphate (ADP) ratio, upregulated AMPKα2 expression, reduced the activity of serum phosphodiesterases (PDEs) and increased myocardial cAMP content. The results of the present study demonstrated that fermented CS attenuated DOX-induced cardiotoxicity by inhibiting myocardial hypertrophy and myocardial damage, ameliorating systolic function and the antioxidant enzyme system, improving cardiac energy metabolism, depressing the activities of PDEs, and by upregulating the cAMP and AMPK signaling pathways. Thus, fermented CS may be a candidate for the prevention of DOX-induced cardiotoxicity, cardiac energy impairment and against a number of cardiac diseases.

Effects of irbesartan on Notch1 signaling pathway in diabetic rats with myocardial injury

To investigate the effects and mechanisms of irbesartan on myocardial injury in diabetic rats, and to analyze the changes of Notch1 signaling pathway in it. Thirty rats were randomly divided into four groups:normal control group (CON, n=6), high calorie group (HC, n=6) and diabetes mellitus group (DM, n=9), irbesartan + diabetes group (Ir + DM, n=9). After modeling 8 weeks later, the body weight ratio and left ventricular weight index were measured and the serum levels of triglyceride (TG) and total cholesterol (TC) were measured by automatic biochemical analyzer. The changes of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in myocardium of rats were determined by the kit and the expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2 assaciated X protein (Bax) protein in myocardium were detected by immunohistochemistry. The expressions of Notch1, Hes-1 and jagged-1 in myocardium of rats were detected by Western blot. Compared with CON group, the levels of heart weight/body weight (H/B), left ventricular weight index(LVWI) and fasting blood glucose(FBG) in HC group were not significantly changed, while the levels of blood lipids, MDA and Bax were increased significantly, and the expressions of SOD, Bcl-2 and Notch1, Hes-1 and Jagged-1 were decreased. Compared with HC group, the levels of H/B, LVWI, FBG, MDA and Bax in DM group were increased significantly, and the levels of SOD, Bcl-2 and Notch1, Hes-1 and Jagged-1 were decreased. The expression of H/B, LVWI, Notch1, Hes-1 and Jagged-1 in Ir+DM group were increased, but there was no significant difference between the other indexes. The H/B and LVWI in Ir + DM group were significantly lower than those in DM group, the levels of blood lipid and blood glucose did not change significantly, but the incidence of oxidative stress and apoptosis was reduced. While Notch1, Hes-1, Jagged -1 protein expressions were increased. Diabetes can induce myocardial injury, and irbesartan has myocardial protective effects through activation of Notch1.

AQP4-knockout aggravation of isoprenaline-induced myocardial injury is mediated by p66Shc and endoplasmic reticulum stress.

Aquaporin 4 (AQP4) is a type of water channel protein that maintains the water balance of cardiomyocytes. However, the physiological role of AQP4 in cardiovascular disease is poorly understood. We wanted to explore whether p66Shc and endoplasmic reticulum stress participates in AQP4 knockout (KO)-mediated cardiac injury. There were two types of mice: AQP4 knockout and wild-type mice. Each type was randomly divided into three groups: Control group, isoprenaline stimulation group (ISO, 1mg/kg, s.c., 5days), and apocynin treatment group (APO, 100mg/kg, p.o., 3days). H9c2 rat cardiomyocytes were cultured for RNA interference of AQP4. Results showed increased left ventricular weight index and more severe myocardial inflammation were induced in AQP4 knockout mice relative to wild-type mice, accompanied by significantly increased levels of the oxidative stress biomarkers MDA and NOX4. In addition, the expressions of p66Shc, ER stress markers PERK, GRP78 and CHOP and proinflammatory factors such as ETA , IL6 and TNFα were upregulated in the myocardium of AQP4 knockout mice or AQP4 siRNA treated cardiomyocytes, whereas CASQ2 was downregulated. ISO stimulation aggravated these abnormalities, which were significantly attenuated by apocynin. This study showed that AQP4 knockout mice were susceptible to cardiac injury induced by ISO. The mechanism was closely connected with p66Shc and proinflammatory factors. Endoplasmic reticulum stress was also involved in the pathological process.

Triptolide Upregulates Myocardial Forkhead Helix Transcription Factor p3 Expression and Attenuates Cardiac Hypertrophy.

The forkhead/winged helix transcription factor (Fox) p3 can regulate the expression of various genes, and it has been reported that the transfer of Foxp3-positive T cells could ameliorate cardiac hypertrophy and fibrosis. Triptolide (TP) can elevate the expression of Foxp3, but its effects on cardiac hypertrophy remain unclear. In the present study, neonatal rat ventricular myocytes (NRVM) were isolated and stimulated with angiotensin II (1 μmol/L) to induce hypertrophic response. The expression of Foxp3 in NRVM was observed by using immunofluorescence assay. Fifty mice were randomly divided into five groups and received vehicle (control), isoproterenol (Iso, 5 mg/kg, s.c.), one of three doses of TP (10, 30, or 90 μg/kg, i.p.) for 14 days, respectively. The pathological morphology changes were observed after Hematoxylin and eosin, lectin and Masson’s trichrome staining. The levels of serum brain natriuretic peptide (BNP) and troponin I were determined by enzyme-linked immunosorbent assay and chemiluminescence, respectively. The mRNA and protein expressions of α- myosin heavy chain (MHC), β-MHC and Foxp3 were determined using real-time PCR and immunohistochemistry, respectively. It was shown that TP (1, 3, 10 μg/L) treatment significantly decreased cell size, mRNA and protein expression of β-MHC, and upregulated Foxp3 expression in NRVM. TP also decreased heart weight index, left ventricular weight index and, improved myocardial injury and fibrosis; and decreased the cross-scetional area of the myocardium, serum cardiac troponin and BNP. Additionally, TP markedly reduced the mRNA and protein expression of myocardial β-MHC and elevated the mRNA and protein expression of α-MHC and Foxp3 in a dose-dependent manner. In conclusion, TP can effectively ameliorate myocardial damage and inhibit cardiac hypertrophy, which is at least partly related to the elevation of Foxp3 expression in cardiomyocytes.

Angiotensin-I-Converting Enzyme Inhibitory Activities and In Vivo Antihypertensive Effects of Sardine Protein Hydrolysate.

In our previous study, an antihypertensive protein hydrolysate was prepared from sardine. This study aimed to investigate the composition of sardine protein hydrolysate (SPH) and it's in vivo antihypertensive effect. SPH was separated sequentially with ultrafiltration and size exclusion chromatography. Fractions with high angiotensin-I-converting enzyme (ACE) inhibitory activity were further analyzed with RP-HPLC and amino acids analysis. Then, SPH was individually oral administrated to spontaneously hypertensive rats (SHR) and normotensive wistar kyoto rats (WKY) for 4 wk. After treatment, the systolic blood pressure (SBP), organindex, oxidative status, serum ACE activity, and serum angiotensin-II (ANG-II) of all the rats were determined. According to the separation and analysis results, 3 main fractions with high ACE-inhibitory activity were obtained with different amino acids composition. The animal experiments results showed that SPH could significantly reduce SBP (P < 0.05 or P < 0.01) within 4 h after a single oral administration. After a chronic oral administration, a steady state of SBP in SHR rats was attained. The heart weight index and left ventricular weight index were significantly reduced (P < 0.05) in SPH-treated SHR rats. The malonyldialdehyde (MDA) levels in organs and serum, serum ACE activity, and serum ANG-II concentration in SPH-treated SHR rats were significantly lowered (P < 0.05 or P < 0.01) as compared to their controls. Meanwhile there was no significant effect (P > 0.05) on those parameters in WKY rats. These results indicate that SPH can decrease blood pressure in SHR rats and not in WKY rats.

Effect of High Thoracic Sympathetic Nerve Block on Serum Collagen Biomarkers in Patients with Chronic Heart Failure

Objectives: The impact of high thoracic sympathetic block (HTSB) on myocardial fibrosis in chronic heart failure (HF) is unclear. Myocardial collagen synthesis can be assessed by measuring circulating biomarkers. We observed the effect of HTSB on serum collagen biomarkers in HF. Methods: Forty-four patients were randomized to a control and a HTSB group. They received routine medications. Repeated epidural injections were given to the HTSB group for 4 weeks. Echocardiography and measurements of serum carboxy-terminal propeptide of procollagen type I (PICP) and amino-terminal propeptide of procollagen type III (PIIINP) were performed at baseline and 4 weeks later. Results: There were significant reductions in left atrial diameter, left ventricular (LV) diameter and volume, LV weight index (LVWI) and serum PICP and PIIINP levels in the HTSB group (p < 0.05). The changes in LV end-systolic volume and ejection fraction (LVEF) were greater in the HTSB group than in the control group (p < 0.05). In the HTSB group, the decreases in PICP and PIIINP were correlated with the decrease in LVWI (PICP: r = 0.695, p = 0.000; PIIINP: r = 0.642, p = 0.001), and the decrease in PICP was negatively associated with the rise in LVEF (r = -0.813, p = 0.000). Conclusion: HTSB reduces myocardial fibrosis in HF, which may accompany the improvement of LV hypertrophy and dysfunction.

Intervention of systolic pressure and left ventricular hypertrophy in rats under cold stress

To investigate the effects of different drugs on systolic blood pressure (SBP) and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats under cold stress. A total of 40 male spontaneously hypertensive rats aged 10 weeks (160~200 g) were given adaptive feeding for 7 days at a temperature of 20±1°C and then randomly divided into control group, cold stress group, metoprolol group, amlodipine group, and benazepril group, with 8 rats in each group. SBP, body weight, and heart rate were measured once a week. After the rats were sacrificed by exsanguination, left ventricular weight (LVW) was measured, and left ventricular weight index (LVWI; mg/g) was calculated. Radioimmunoassay was used to measure the concentrations of endothelin-1 (ET-1) and angiotensin-II (Ang-II) in plasma and myocardium, and the chemical method was used to measure the concentrations of nitric oxide (NO) in plasma and myocardium. RT-PCR was used to measure the mRNA expression of endothelin-A receptor. Compared with the cold stress group, all medication groups showed significant reductions in SBP since week 5 (P<0.05). The cold stress group showed a significant increase in LVWI compared with the control group (3.38±0.27 mg/g vs 2.89±0.19 mg/g, P<0.05). The amlodipine group showed a significant reduction in LVWI compared with the cold stress group (2.98±0.28 mg/g vs 3.38±0.27 mg/g, P<0.05). The cold stress group showed a significant reduction in plasma NO concentration compared with the control group (104.9±19.5 μmol/L vs 129.3±17.8 μmol/L, P<0.05) ; compared with the cold stress group, all the medication groups showed significant increases in blood NO concentration (P<0.05). The cold stress group showed a significant increase in myocardial ET-1 concentration compared with the control group (6.3±1.5 pg/100 mg vs 4.5±1.9 pg/100 mg, P<0.05) ; compared with the cold stress group, the amlodipine group showed a significant reduction in myocardial ET-1 concentration (4.4±1.0 pg/100 mg vs 6.3±1.5 pg/100 mg, P<0.05). The cold stress group had significantly higher mRNA expression of endothelin-A receptor than the control group (0.86±0.23 vs 0.45±0.16, P<0.01) ; compared with the cold stress group, the amlodipine group showed a significant reduction in the mRNA expression of endothelin-A receptor (0.41±0.14 vs 0.86±0.23, P<0.01). Amlodipine can reduce the increase in SBP and inhibit LVH in spontaneously hypertensive rats under cold stress.