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Title: The Role of cAMP in the Enhancement of Vascular Endothelial Growth Factor (VEGF) Release from Human Macrophages by β2-adrenoceptor Agonists
Authors: Sara Nashaat El-Zohairy 
Supervisor: Prof. Charles I. Ezeamuzie
Keywords: Asthma;β2-adrenoceptor agonists;cAMP;VEGF
Issue Date: 2012
Publisher:  Kuwait university - college of graduate studies
Abstract: Asthma is a chronic disease that exerts a high morbidity burden on the sufferers and a heavy economic burden on society. The β2-adrenoceptor agonists are effective bronchodilators widely used in the treatment of the disease, but their inability to affect the inflammatory component of the disease limits their overall usefulness. In fact, their use in monotherapy may result in the progression of the disease over time. One of the reasons for this is thought to be that these drugs are also able to enhance the release of some pro-inflammatory mediators, especially VEGF, an angiogenic factor that has been implicated in the pathophysiology of asthma. The mechanism by which β2-agonists enhance VEGF release is currently unclear. The purpose of this study was, therefore, to investigate the role of cAMP and its downstream pathways (EPAC or PKA) in the enhancement of VEGF release from human macrophages by β2-agonists. Human U937 cells were differentiated into macrophages by culturing them for 48 h in the presence of phorbol 12- myristate 13-acetate. The enhancing effect of different β2-agonists on LPS-induced release of VEGF from the differentiated cells was then studied and compared to their effect on TNF-α release. Moreover, the ability of β2-agonists to increase cAMP release was also investigated. The released VEGF and the intracellular cAMP were measured by enzyme immunoassay. Finally, the involvement of the PKA and/or EPAC pathways was investigated using selective pathway agonists and antagonists. The LPS-induced VEGF release was enhanced by all β2- agonists in a concentration-dependent manner, whereas TNF-α release was inhibited. The rank order of β2-agonist potency was formoterol > salmeterol > isoprenaline > salbutamol ≥ procaterol, which was similar for both VEGF enhancement and TNF-α inhibition. Both the nonselective β-antagonist propranolol and the β1- and β2-selective antagonists, atenolol and ICI 118551, respectively, inhibited isoprenaline-induced enhancement of VEGF release in a v competitive manner. However, ICI 118551 (KB= 2.15 ± 0.90 nM) was more effective than atenolol (KB= 8.63 ± 2.18 nM). These results suggest that although β1-receptors may also be involved in the release of VEGF by β-agonists, β2-receptors are the pre-dominant subtype involved. The results also established the involvement of cAMP as the second messenger mediating the release of VEGF by β2-agonists. The use of several cAMP pathway agonists and antagonists revealed that the PKA pathway, rather than the EPAC pathway, is responsible for the cAMPdependent VEGF release by β2-agonists.
Appears in Programs:0550 Pharmacology (M.Sc.)

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