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Diabetes mellitus is a prominent risk factor for cardiovascular diseases. Diabetic cardiomyopathy is an important complication of the heart independent of hypertension and coronary artery disease and is accompanied by cardiac hypertrophy. Cardiac hypertrophy easily leads to heart failure, which is a leading cause of morbidity and mortality. Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which has various beneficial roles in the cardiovascular system, and exendin-4 is a highly potent glucagon-like peptide 1 receptor agonist. However, the role of GLP-1 in cardiac hypertrophy remains unknown. Our study revealed that exendin-4 treatment ameliorated phenylephrine (PE)-induced cardiac hypertrophy, which presented as decreased cardiac hypertrophic markers (ANP, BNP, and β-MHC) and cell surface area. This condition was significantly reversed upon treatment with the GLP-1 receptor antagonist exendin9-39. We also discovered that Erk1/2 and AMPK signaling pathways were involved in this process. Furthermore, our data demonstrate that the AMPK inhibitor compound C inhibited the anti-hypertrophic effect of exendin-4, which is associated with the mTOR/p70S6K/4-EBP1 signaling pathway. Finally, exendin-4 enhanced the anti-hypertrophic effect of rapamycin. In summary, our study disclosed that exedin-4 inhibits cardiac hypertrophy by upregulating GLP-1 receptor expression and activating the AMPK/mTOR signaling pathway.

The nonpeptide AVE0991 is expected to be a putative new drug for cardiovascular diseases. However, the mechanisms for the cardioprotective actions of AVE0991 are still not fully understood. We planned to determine whether AVE0991 attenuates the angiotensin II (AngII)-induced myocardial hypertrophy and whether these AVE0991 effects involved transforming growth factor beta1 (TGF-beta1) and Smad2. A rat model of neonatal myocardial hypertrophy was induced by AngII. The AngII group significantly increased in protein content, surface area, and [(3)H]leucine incorporation efficiency by cardiomyocytes, compared to those of the control group (P < 0.01). The AngII group also had elevated TGF-beta1 and Smad2 expression (P < 0.01). These AngII-induced changes were significantly attenuated by AVE0991 in a dose-dependent manner. In our study, these actions of AngII (10(-6) mol/l) were significantly inhibited by both concentrations of AVE0991 (10(-5) mol/l and 10(-7) mol/l). Moreover, the high AVE0991 group had significantly better inhibition of myocardial hypertrophy than the low AVE0991 group. Meanwhile, the beneficial effects of AVE0991 were completely abolished when the cardiomyocytes were pretreated with Ang-(1-7) receptor antagonist A-779 (10(-6) mol/l). These results suggested that AVE0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-beta1/Smad2 signaling.

The posterior wall of left atrium plays an important role in atrial fibrillation (AF) recurrence, but the benefit of left atrial posterior wall isolation (PWI) remains still unclear. The objective was to evaluate the benefit of PWI in radiofrequency ablation. PubMed and the Web of Science were searched in September 2015. Studies comparing catheter ablation with PWI [PWI(+)] vs. ablation without PWI [PWI(−)] were included. We performed a meta-analysis to assess atrial arrhythmia recurrence, procedure-related complications, and procedural time. Five studies with 594 AF patients were included. Compared with PWI(−), PWI(+) resulted in a significantly lower atrial arrhythmia recurrence rate (relative risk [RR] 0.81, 95 % confidence interval [CI] 0.68–0.97, p = 0.02), which was largely driven by the decreased AF recurrence (RR 0.55, 95 % CI 0.35–0.86, p = 0.009). Recurrence rates of atrial tachycardia/flutter (AT/AFL) were comparable between two groups (RR 1.16, 95 % CI 0.85–1.58, p = 0.34). There were no significant differences in procedure-related complications (RR 1.07, 95 % CI 0.45–2.53, p = 0.89) and procedural times (weight mean difference 0.88, 95 % CI −7.29–9.06, p = 0.83). This meta-analysis shows that with comparable procedure-related complications and procedural time, ablation with PWI reduces AF recurrence.

Cardiomyocyte stretching has been reported to be a major trigger for brain natriuretic peptide (BNP) release; however, an increase in circulating BNP is observed in patients with acute myocardial ischemia in the absence of increased left ventricular wall stress or cardiomyocyte stretching. In the present study, to investigate the direct and independent effects of acute myocardial ischemia on BNP expression and its mechanism, we established an in vitro glucose-free ischemia and hypoxia injured model of cultured rat cardiomyotes and proved hypoxia upregulated expressions of interleukin-6(il-6) and BNP. Further treatment with il-6 elicited dose- and time-dependent increases in BNP mRNA and protein expression as well as an upregulation in transforming growth factor-β1 (TGF-β1)/Smad2 expression, which was partially suppressed by a neutralizing antibody. In conclusion, our study showed that acute myocardial ischemia can directly upregulate BNP expression at the translational and transcriptional levels through the action of il-6, and this process is associated with the upregulation of TGF-β1/Smad2 signal path.

Summary 1. Previously, we showed that long-term treatment of rats after myocardial infarction (MI) with B-type natriuretic peptide (BNP) prevented ventricular remodelling. However, it is unclear whether long-term BNP treatment affects cardiac hypertrophy and, if so, its mechanism of action. In the present study, we investigated the effects of long-term BNP treatment on cardiac hypertrophy and the molecular mechanisms involved. 2. Cardiac hypertrophy was established in rats by ligation of the left anterior descending coronary artery. After treatment with BNP (5 or 15 μg/kg per day) for 8 weeks, indices of cardiac hypertrophy were determined. In separate in vitro experiments, cardiomyocyte hypertrophy was induced by treatment of cardiomyocytes with 10−6 mol/L angiotensin (Ang) II for 48 h and cell surface area and [3H] incorporation were measured. Transforming growth factor (TGF)-β1 and smad7 mRNA and protein expression in vivo and in vitro were detected using reverse transcription–polymerase chain reaction and western blotting. 3. Long-term BNP treatment dose-dependently attenuated cardiac hypertrophy and improved cardiac function in rats after MI. Furthermore, BNP attenuated the upregulation of TGF-β1 and downregulation of smad7 mRNA and protein expression. The in vitro experiments further proved that BNP inhibited cardiac hypertrophy and changes in the TGF-β1/smad7 pathway, which were completely blocked by the cyclic GMP-dependent protein kinase (PKG) inhibitor, KT5823 (cells were treated with 10−6 mol/L KT5823 for 48 h). 4. The results of the present study demonstrate that long-term treatment of rats with BNP dose-dependently attenuates cardiac hypertrophy and that this is associated with downregulation of TGF-β1 and upregulation of smad7 via PKG signalling. Long-term BNP treatment may be a new therapeutic strategy to prevent cardiac hypertrophy and progression to heart failure.

Although short-term B-type natriuretic peptide (BNP) treatment has been shown to be effective for decompensated congestive heart failure, little is known about the effects of long-term BNP treatment in ventricular remodeling and heart failure in response to myocardial infarction. The aim of the present study was to investigate the effects of long-term BNP treament on ventricular remodeling and heart failure after myocardial infarction in rats. Myocardial infarction was induced by ligating the left anterior descending coronary artery. The surviving rats were randomly divided into four groups: 1) vehicle-treated myocardial infarction group (‘vehicle-treated group’), 2) rats treated with low-dose BNP (‘low BNP group’), 3) rats treated with high-dose BNP (‘high BNP group’), 4) sham-operated group. Eight weeks after the operation, rats were sacrificed. Compared with the sham-operated group, the vehicle-treated group had significantly higher collagen deposition and angiotensin II levels (P < 0.01) and a significantly lower cardiac function (P < 0.05). Both BNP-treated groups had significant improvement of these indexes compared with the vehicle-treated group (P < 0.01). The high BNP group had significantly less collagen deposition and better cardiac function than the untreated and low BNP groups. Moreover, the mRNA and protein expression of TGFβ1 and Smad2 in the vehicle-treated group was significantly higher than in the sham-operated group (P < 0.01). Both BNP-treated groups had a suppression of TGFβ1 and Smad2 expression (P < 0.01). In conclusion, long-term treatment with BNP prevents ventricular remodeling and deterioration of cardiac function in a dose-dependent fashion, a process that may be associated with the inhibition of TGFβ1/ Smad2 signaling.

Cardiac hypertrophy is the pathological basis of the development of various cardiovascular diseases and is a major independent risk factor of cardiovascular morbidity and mortality. Glucagon-like peptide 1 (GLP-1), an incretin peptide released from the intestine, exerts various cardioprotective

Objectives We have shown that interleukin-6 (IL-6) upregulates brain natriuretic peptide (BNP) expression in rat cardiomyocytes under ischaemic conditions, partly via the transforming growth factor β1 (TGF-β1)/SMAD2 signal pathway. Studies have shown that the IL-6/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling pathway plays a significant role in myocardial ischaemic injury. We have questioned whether JAK2 and STAT3 proteins also participate in IL-6-mediated regulation of BNP in neonatal rat cardiomyocytes. Methods Direct drug intervention with IL-6 showed that IL-6 independently activates the JAK2/STAT3 pathway in neonatal rat cardiomyocytes. Results Moreover, increased phosphorylation of the STAT3 protein was first detectable after 5 min of IL-6 stimulation; phosphorylation was highest at 15 min and returned to basal level within 1 h. A specific inhibitor was then chosen to investigate the role of the JAK2/STAT3 pathway. Pretreatment with 10 mM AG490, a specific inhibitor for JAK2 protein, could suppress the increase in BNP levels induced by the administration of 10 ng/ml of IL-6, and maximal inhibition is achieved at a 50 mM concentration of AG490. Furthermore, combinational inhibition with neutralising antibody, which blocks the TGF-β1/SMAD2 pathway, and AG490 failed to completely suppress the increase in BNP levels. Conclusions Thus, apart from the TGF-β1/SMAD2 signalling pathway, the JAK2/STAT3 pathway is also important in the IL-6-mediated regulation of BNP in neonatal cardiomyocytes; other signalling pathways may also be involved in this process.