Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β‐adrenoceptors transduce the signal produced by catecholamine stimulation via G_s proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β‐adrenoceptors become hyperstimulated. The hyperstimulated β₁‐adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β₂‐adrenoceptor‐mediated G_i signalling. However, β₂‐adrenoceptor‐G_i signalling negates the stimulatory effect of the G_s signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β₁‐ and β₂‐adrenoceptors and β₂‐adrenoceptor‐mediated β‐arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β‐adrenoceptor subtype signalling in the failing heart, and conclude that G_i‐biased β₂‐adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β₂‐adrenoceptor‐G_s signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a G_s‐biased β₂‐adrenoceptor agonist and a β₁‐adrenoceptor antagonist in combination. This combination treatment normalizes the β‐adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies.

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This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ACEI

ACE inhibitors

CaMKII

Ca²⁺/calmodulin‐dependent kinase II

ct

carboxy terminus

EGFR

epidermal growth receptor

Epac

exchange protein directly activated by cAMP

G_i

inhibitory G protein

GRK

GPCR kinase

G_s

stimulatory G protein

HF

heart failure

PKA

cAMP‐dependent protein kinase

SNS

sympathetic nervous system

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Cancer‐generated lactic acid: a regulatory,immunosuppressive metabolite?

The common preference of cancers for lactic acid‐generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti‐cancer immune response through maintaining a relatively low pH in their micro‐environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro‐environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti‐cancer immune response. Cancer‐generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a ‘waste product’. This paradigm shift can have major impact on therapeutic strategy development. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The application of novel mussel-inspired compounds in dentistry

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Skeletal and airway stability after mandibular setback in patients with mandibular prognathism: A systematic review

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FISSURE SEALANT IN A NUTSHELL. EVIDENCE-BASED META-EVALUATION OF SEALANTS’ EFFECTIVENESS IN CARIES PREVENTION AND ARREST

ObjectiveThis meta-evaluation aimed to summarize all available evidence regarding different fissure sealants on occlusal caries prevention, arrest, retention rate, adverse effect, and cost-effectiveness; when compared with no intervention, other preventive or minimally-invasive procedures.Materials and MethodsThe systematic reviews and meta-analyses were identified via four electronic databases and manual searching. Two independent reviewers performed study selection, data extraction, quality assessment with AMSTAR-2.ResultsAmong the 366 records yielded, 38 systematic reviews were identified as eligible 24 of them included meta-analyses. Moderate evidence has supported the efficacies of resin-based sealants (RBS) in occlusal caries prevention, arrest and cost-effectiveness compared to no interventions. Low to very low certainty of evidence suggested similar effectiveness of glass-ionomer cements in caries prevention with RBS and more superior performance of resin infiltration in arresting non-cavitated occlusal lesions.ConclusionThis meta-evaluation supports the use of RBS on permanent molars to reduce occlusal caries occurrence, arrest lesion progression and alleviate oral health inequalities between individuals of different socioeconomic status. This meta-evaluation also advocates further research on glass-ionomer cements and resin infiltration with respect to their efficacies in caries prevention and arrest.     

Ultrasonography-guided arthrocentesis versus conventional arthrocentesis in treating internal derangement of temporomandibular joint: a systematic review

Clinical Oral Investigations - This systematic review assessed the clinical question: ‘Does ultrasonography (USG)-guided arthrocentesis provide better outcomes than conventional...