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β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors ( β2- TG), and the effect of cardiac pressure overload. β2- TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2- TGs showed upregulated expression of vascular endothelial growth factor ( VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein ( CREB), and increased recruitment of phospho- CREB, CREB-binding protein ( CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction ( TAC), angiogenic signaling in β2- TGs was inhibited within 1 week after TAC. β2- TG hearts, but not controls, exposed to pressure overload for 1-2 weeks showed significant increases from baseline in phosphorylation of Ca2+/calmodulin-dependent kinase II (Ca MKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho- CREB, p300 and CBP recruited to the CREB-responsive element ( CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non- TG mice with TAC developed compensatory hypertrophy, (2- TGs exhibited exaggerated hypertrophic growth at week-1 post- TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2 AR/ CREB/ VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated Ca MKII and p53, leading to impaired angiogenesis and functional decompensation. [ABSTRACT FROM AUTHOR]

1. The purpose of the present study was to evaluate differences in the AMP-activated protein kinase (AMPK) phosphorylation sites in cardiac hypertrophy induced byl-thyroxine and angiotensin (Ang) II. 2. Cardiac hypertrophy was induced in wild-type and AMPKα2-knockout mice by treatment with 1 mg/kg, i.p., thyroxine or 1.44 mg/kg per day AngII for 14 days. The phenotype of the hypertrophy was evaluated using echocardiographic measurments and histological analyses. The phosphorylation of AMPK at α-Ser485/491 and α-Thr172 was determined by western blot analysis. 3. In wild-type mice, the phosphorylation of AMPKα-Ser485/491 was significantly elevated in the AngII-treated group, but not in the thyroxine-reated group, compared with the vehicle control group. In contrast, the phosphorylation of AMPKα-Thr172 was significantly increased by thyroxine, but not AngII, treatment compared with the vehicle control group. Furthermore, knockout of the AMPKα2 subunit abolished phosphorylation at the α-Ser485/491 site and significantly suppressed phosphorylation at the α-Thr172 site, resulting in alleviation of thyroxine- but not AngII-induced hypertrophy. 4. In conclusion,l-thyroxine and AngII induce the phosphorylation of distinct sites of AMPK in cardiac hypertrophy. Phosphorylation of AMPK α-Thr172 may contribute to thyroxine-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β2-adrenergic receptors (β2-ARs) are important targets in COPD therapy. β2-adrenergic receptor autoantibodies (β2-AAbs), which may directly affect β2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2-AAbs are associated with smoking-related emphysema. [ABSTRACT FROM AUTHOR]

In order to enhance the performance of universality and robustness of the numerical optimization algorithms, an ensemble of evolution algorithm based on self-adaptive learning population search techniques (EEA-SLPS) is proposed. EEA-SLPS integrates three self-adaptive learning population based algorithms from different fields of stochastic search techniques. One sub-algorithm is designed in this paper, the other two are recently proposed in relevant literature. The whole individual population is divided into three sub-populations, and each sub-algorithm is employed to evolve each sub-population respectively in parallel manner during the whole search process. In each sub-algorithm, both search strategies and parameters are gradually self-adaptive in different stages of the search process. The performance of EEA-SLPS is extensively evaluated on a suite of 26 bound-constrained test functions with different characteristics. By comparing with several state-of-the-art algorithms, the experimental results clearly verify the advantages of EEA-SLPS. [ABSTRACT FROM AUTHOR]

Abstract: We used the technique of single particle tracking (SPT) with high tempo-spatial resolution to efficiently explore the route and mechanism for the transport of α1A-adrenergic receptor (α1A-AR) in real time in living cells. We found that the initial transport of α1A-AR in cells depended on actin filaments with the velocity of 0.2μm/s and exhibited discrete 33-nm steps. It was noted that the step size, the rate constant, and the velocities were in accordance with the character of single myosin in vitro, implying that while transporting each endosome myosins did not work in the “tug-of-war” mode and that they did not adopt the strategy to boost up transporting speed by working coordinately. These results provided insight into the mechanism of GPCR transport in vivo. [Copyright &y& Elsevier]

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]

The autonomic nervous system consists of the sympathetic nervous system and the parasympathetic nervous system. These two systems control the heart and work in a reciprocal fashion to modulate myocardial energy metabolism, heart rate as well as blood pressure. Multiple cardiac pathological conditions are accompanied by autonomic imbalance, characterized by sympathetic overactivation and parasympathetic inhibition. Studies have shown that overactive sympathetic nervous system leads to increased cardiac inflammatory reaction. Orchestrated inflammatory response serves to clear dead cardiac tissue and activate reparative process, whereas excessive inflammation may result in pathological cardiac remodeling. Since the discovery of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway (CAP), the protective effects of the parasympathetic nervous system in cardiac inflammation have attracted more attention recently. In this review, we summarized the role and underlying mechanisms of the sympathetic and parasympathetic nervous systems in cardiac inflammation, in order to provide new insight into cardiac inflammatory response in cardiovascular diseases.

Prostaglandin (PG) E 2 plays critical roles during pregnancy and parturition. Emerging evidence indicates that human labour is an inflammatory event. We sought to investigate the effect of PGE 2 on the output of proinflammatory cytokines in cultured human uterine smooth muscle cells (HUSMCs) from term pregnant women and elucidate the role of subtypes of PGE 2 receptors (EP 1 , EP 2 , EP 3 and EP 4 ). After drug treatment and/or transfection of each receptor siRNA, the concentrations of inflammatory secreting factors in HUSMCs culture medium were detected by the corresponding ELISA kits. The results showed that, PGE 2 increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) output, decreased chemokine (c-x-c motif) ligand 8 (CXCL8) output in a dose-dependent manner, but had no effect on IL-1β and chemokine (c-c motif) ligand 2 (CCL-2) secretion of HUSMCs. EP 1 /EP 3 agonist 17-phenyl-trinor-PGE 2 stimulated IL-6 and TNFα whilst suppressing IL-1β and CXCL8 output. The effects of 17-phenyl-trinor-PGE 2 on IL-1β and CXCL8 secretion were remained whereas its effect on IL-6 and TNFα output did not occur in the cells with EP 3 knockdown. The stimulatory effects of 17-phenyl-trinor-PGE 2 on IL-6 and TNFα were remained whereas the inhibitory effects of 17-phenyl-trinor-PGE 2 on IL-1β secretion was blocked in the cells with EP 1 knockdown. Either of EP 2 and EP 4 agonists stimulated IL-1β and TNFα output, which was reversed by EP 2 and EP 4 siRNA, respectively. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked EP 1 /EP 3 modulation of TNFα and CXCL8 output. PI3K inhibitor LY294002 and P38 inhibitor SB202190 blocked 17-phenyl-trinor-PGE 2 -induced IL-1β and IL-6 output, respectively. The inhibitors of adenylyl cyclase and PKA prevented EP 2 and EP 4 stimulation of IL-1β and TNFα output, whereas PLC and PKC inhibitors blocked EP 2 - and EP 4 -induced TNFα output but not IL-1β output. Our data suggest that PGE 2 receptors exhibit different effects on the output of various cytokines in myometrium, which can subtly modulate the inflammatory microenvironment in myometrium during pregnancy.