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Chronic injection with the β-adrenoceptor (β- AR) agonist isoproterenol ( ISO) has been commonly used as an animal model of β- AR-induced cardiac remodelling and heart failure. This ISO-treated model usually exhibits significantly decreased conscious heart rate ( HR). However, the HR in treatment groups is usually adjusted to the same levels by anaesthesia to assess cardiac geometry and function. In the present study, we report a method of echocardiographic assessment that represents the true cardiac geometry and function under conditions of ISO withdrawal., Briefly, C57BL/6 mice were treated with 5 mg/kg per day ISO for 12 weeks. Cardiac geometry and function were assessed by high-resolution echocardiography in vehicle (saline) - and ISO-treated mice that were either conscious or anaesthetized using different concentrations of isoflurane., The cardiac β- AR response was decreased in ISO-treated mice, as evidenced by markedly decreased conscious HR. Vehicle- and ISO-treated mice did not differ in terms of cardiac geometry or function when HR was adjusted to the same level (400 b.p.m.) in both treatment groups, but cardiac geometry and function did differ when a low (1%) rather than high (1.5% or 2%) isoflurane concentration was used to adjust HR. Furthermore, 3 day ISO withdrawal eliminated the difference in conscious HR between the two groups. In addition, the groups differed in cardiac geometry and function regardless of the isoflurane concentration used., In conclusion, using isoflurane to decrease the HR of treated groups to the same level may mask left ventricular dysfunction in ISO-treated mice. Withdrawal of ISO eliminated the difference in basal HR between the ISO-treated and control groups on echocardiography, allowing a more accurate assessment of cardiac pathological and functional changes. [ABSTRACT FROM AUTHOR]

Aim:To investigate the molecular mechanisms underlying the antitumor activity of cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata.Methods:Human osteosarcoma cell line SaOS2 was used. MTT assay, Hoechst 33342 nuclear staining, flow cytometry, Western blotting and nude mouse xenografts of SaOS2 cells were applied to examine the antitumor activity of CEP in vitro and in vivo. The expression levels of STAT3 and its downstream signaling molecules were measured with Western blotting and immunochemistry analysis. The activity of STAT3 was detected based on the phosphorylation level of STAT3, luciferase gene reporter assay and translocation of STAT3 to the nucleus.Results:Treatment of SaOS2 cells with CEP (2.5-20 μmol/L) inhibited the cell growth in a concentration- and time-dependent manner. CEP (10 μmol/L) caused cell cycle arrest at G1 phase and induced apoptosis of SaOS2 cells. CEP (10 and 15 μmol/L) significantly decreased the expression of STAT3 in SaOS2 cells. Furthermore, CEP (5 and 10 μmol/L) significantly inhibited the expression of target genes of STAT3, including the anti-apoptotic gene Bcl-xL and the cell cycle regulators c-Myc and cyclin D1. In nude mouse xenografts of SaOS2 cells, CEP (20 mg·kg−1·d−1, ip for 19 d) significantly reduced the volume and weight of the tumor.Conclusion:Our findings suggest that inhibition of STAT3 signaling pathway is involved in the anti-tumor activity of CEP. [ABSTRACT FROM AUTHOR]

Aim:To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect.Methods:Wild type and AMPKα2 knockout (AMPKα2−/−) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg−1·d−1) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting.Results:Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2−/− mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2−/− mice.Conclusion:Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

1. The mouse is the preferred species for gene targeting as a tool for research into the heart and heart development. The developmental features of the geometry and function of the heart in young mice are not well defined and cardiac functional responses following stimulation of β-adrenoceptors have not been investigated. 2. Using the VisualSonic (Toronto, ON, Canada) high-resolution ultrasound system, we investigated male C57BL/6 mice at 0.5–18 weeks of age. Echocardiography was performed at baseline and repeated after administration of the β-adrenoceptor agonist isoproterenol (4 μg/kg). 3. The geometry of the left ventricle became mature 2 weeks after birth. A significant decline in left ventricular contractile function occurred at 2–3 weeks of age. 4. Inotropic and chronotropic responses to isoproterenol were significantly weaker in mice at a weaning age < 2 weeks compared with adult mice (heart rate increment 3 ± 3% vs 32 ± 4%, respectively; fractional shortening increment 19 ± 5% vs 78 ± 8%, respectively; P < 0.001). 5. In conclusion, significant changes occur in mice from birth until weaning with respect to the topography, function and β-adrenoceptor responsiveness of the heart. The results of the present study provide a reference point for future studies in genotyping cardiac function during the postnatal phase in genetically engineered mice. [ABSTRACT FROM AUTHOR]

1. In the present review, we focus on the genetic mouse models for transforming growth factor (TGF)-β signalling, which have aided our understanding on the role of the TGF-β signalling pathway in cardiac hypertrophy/fibrosis and the molecular mechanisms involved. 2. Knockout of TGF-β is embryonic lethal, indicating that TGF-β signalling plays an important role in embryonic development. In order to avoid this defect, many mouse strains with cardiac-specific targeted genes in TGF-β signalling have been developed. 3. The TGF-β family signalling pathway includes Smad-dependent and -independent pathways. 4. Investigations using the genetic mouse models have confirmed and uncovered the involvement of the TGF-β/TGF-β-activated kinase 1 (TAK1) pathway in the development of cardiac hypertrophy and fibrosis. Although the downstream cascade of TAK1-induced cardiac hypertrophy remains only partially defined, recent research indicates that the TGF-β/TAK1/p38 pathway is involved in cardiac fibrosis 5. Smad-dependent signalling may not be involved in, or may even be inhibitory for, cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported that cardiac fibroblasts, but not cardiomyocytes, are served as the predominant source of IL-6 after isoproterenol stimulation in mouse myocardium. The present study investigated the molecular mechanism of isoproterenol-mediated secretion of IL-6 in mouse cardiac fibroblasts. Treatment of cells with isoproterenol-induced a time-dependent accumulation of IL-6, which was mediated by β2-adrenergic receptor (AR), the preponderant β-AR subtype in cardiac fibroblasts. Isoproterenol-induced secretion of IL-6 was mainly mediated by Gs-AC-cAMP signaling cascade and could be negatively regulated by Gi and PI3K. Surprisingly, the effect of cAMP was independent of protein kinase A and the exchange protein directly activated by cAMP (Epac)-Rap1 pathway and suggests the existence of a novel cAMP-dependent mechanism. p38 MAPK inhibitor SB203580, but not extracellular regulated protein kinase inhibitor, abrogated isoproterenol-induced IL-6 release in cardiac fibroblasts and mouse myocardium. Interestingly, p38 MAPK could also be positively regulated by Gs-AC-cAMP but negatively regulated by Gi-PI3K pathway. Finally, multiple transcription factors (AP-1, C/EBP, NF-κB and CREB) regulating the IL-6 gene are activated in response to isoproterenol stimulation, which may provide essential linkage between upstream cAMP-p38 MAPK signaling cascade and downstream IL-6 gene transcription. The present results suggest that β2-AR mediates IL-6 production through a noncanonical cAMP responsible pathway and p38 MAPK. [Copyright &y& Elsevier]