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Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.

Coal and gas outburst seriously threatens the safety of underground coal mining. With the increase in coal mining depth, the geological conditions of coal mines become complicated, which adversely affects the safety of coal mining production. Prominent prediction is an important link to reduce the damage caused by outburst accidents. This study investigated the prediction model of coal and gas outburst. On the basis of the analysis of the gas geological factors of coal and gas outburst, a prediction system including 3 major indices (i.e., gas, coal, and crustal stress indices) and 12 minor indices (e.g., gas pressure and tectonic coal thickness) was established. A multi-index coupling prediction model based on the improved input and output of the gray correlation model was proposed. Network analysis and multi-class distance discriminant method were also comprehensive applied to improve the accuracy of coal and gas outburst index prediction. On the basis of the comprehensive analysis of the gas geological factors of coal and gas outburst, the model calculates the weight of the prediction index, classifies the possible grade of the outburst, and derives the discriminant formulas to discriminate the possibility of outbursts. Taking the Pingdingshan No. 8 coal mine as an example, the model estimated the probability of coal and gas outburst in eight sets of prediction samples. The predicted results are consistent with the actual conditions, provide technical support for coal mine and gas outburst prevention, and prove the accuracy and applicability of the multi-index coupling prediction model.

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]

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]

Aims: Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult., Methods and Results: Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis., Conclusion: Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)