Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells

Growcott, Ellena; Spink, Karen G.; Ren, Xiaohui; Afzal, Saliha; Banner, Katharine H.; Wharton, John

doi:10.1186/1465-9921-7-9

Cited by 45 publications

(38 citation statements)

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“…26 More precisely, phosphodiesterase-4 are enzymes that break a phosphodiester bond, and these enzymes have been identified as new potential therapeutics. 35 The fourth SNP pair involves rs2830075 and rs2163786 in susceptibility to RA. These two SNPs are located in APP and APBB3 (Fe65L2) genes.…”

Section: Discussionmentioning

confidence: 99%

Using biological networks to search for interacting loci in genome-wide association studies

et al. 2009

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Genome-wide association studies have identified a large number of single-nucleotide polymorphisms (SNPs) that individually predispose to diseases. However, many genetic risk factors remain unaccounted for. Proteins coded by genes interact in the cell, and it is most likely that certain variants mainly affect the phenotype in combination with other variants, termed epistasis. An exhaustive search for epistatic effects is computationally demanding, as several billions of SNP pairs exist for typical genotyping chips. In this study, the experimental knowledge on biological networks is used to narrow the search for two-locus epistasis. We provide evidence that this approach is computationally feasible and statistically powerful. By applying this method to the Wellcome Trust Case -Control Consortium data sets, we report four significant cases of epistasis between unlinked loci, in susceptibility to Crohn's disease, bipolar disorder, hypertension and rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

Using biological networks to search for interacting loci in genome-wide association studies

et al. 2009

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“…GNAS also couples receptors to the effector enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Generation of cAMP is critical to several key pathways involving cellular growth and apoptosis, particularly in several tumor types and in vascular tissue (62)(63)(64)(65)(66)(67). These activities are particularly relevant to PAH both in terms of the pathophysiologic underpinnings of the disease and the beneficial effects on clinical outcome with prostacyclins, whose main activity is mediated via activation of cAMP (68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension

Benza

Gomberg‐Maitland

DeMarco

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs).Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Singlenucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort.Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months.Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

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“…Inflammatory cells, the number of which correlates with the degree of pulmonary endothelial dysfunction, are also found in the pulmonary artery wall of COPD patients, and the risk of pulmonary hypertension increases with the severity of low-grade systemic inflammation [31,32]. The role of low-grade chronic inflammation in COPD comorbidity and, especially, in nutritional and muscular impairment, remains a matter of debate.…”

Section: Copd and Inflammation: Different Mechanisms For Different Phmentioning

confidence: 99%

Beyond corticosteroids: future prospects in the management of inflammation in COPD

Roche¹,

Marthan²,

Berger³

et al. 2011

Eur Respir Rev

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Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease-antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities.Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators.Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

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Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells

Cited by 45 publications

References 50 publications

Using biological networks to search for interacting loci in genome-wide association studies

Using biological networks to search for interacting loci in genome-wide association studies

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension

Beyond corticosteroids: future prospects in the management of inflammation in COPD

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