Division of Cardiovascular Medicine
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Adenosine is generated in response to tissue hypoxia, cell stress or damage and exerts effects in essentially every organ system by interacting with four G protein-coupled receptors designated A1, A2A, A2B, and A3. A central hypothesis of our laboratory is that in pathophysiological situations associated with tissue hypoxia, when local levels of extracellular adenosine are considerably increased, A2B receptors become an integral part of a feedback mechanism aimed to restore oxygen supply to the affected tissues. Once activated, these receptors contribute to hypoxia-induced neovascularization by inducing synthesis of angiogenic factors molecules.
Although adenosine acts in most cases as a protective metabolite in various tissues, it serves as amplifier of lung inflammation and damage. Adenosine triggers asthma in asthmatic patients but not in normals, and blockade of adenosine receptors appears to be the mechanisms of action of theophylline and other xanthines. Our research is also aimed at identifying the specific receptor type that mediates adenosine actions in asthmatics. It is hoped that this research will lead to the development of more potent and specific anti-asthmatic drugs with lesser side effects than theophylline.
Our Collaborators :
· Ryzhov, S, Zaynagetdinov, R, Goldstein, AE, Matafonov, A, Biaggioni, I, Feoktistov, I. Differential role of the carboxy-terminus of the A(2B) adenosine receptor in stimulation of adenylate cyclase, phospholipase Cbeta, and interleukin-8. Purinergic Signal, 5(3), 289-98, 2009. PMCID:2717310
· Zaynagetdinov, R, Ryzhov, S, Goldstein, AE, Yin, H, Novitskiy, SV, Goleniewska, K, Polosukhin, VV, Newcomb, DC, Mitchell, D, Morschl, E, Zhou, Y, Blackburn, MR, Peebles Jr, RS, Biaggioni, I, Feoktistov, I. Attenuation of Chronic Pulmonary Inflammation in A2B Adenosine Receptor Knockout Mice. Am J Respir Cell Mol Biol, , , 2010.
· Novitskiy, SV, Ryzhov, S, Zaynagetdinov, R, Goldstein, AE, Huang, Y, Tikhomirov, OY, Blackburn, MR, Biaggioni, I, Carbone, DP, Feoktistov, I, Dikov, MM. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood, 112(5), 1822-31, 2008. PMCID:2518889
· Ryzhov, S, Novitskiy, SV, Zaynagetdinov, R, Goldstein, AE, Carbone, DP, Biaggioni, I, Dikov, MM, Feoktistov, I. Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia, 10(9), 987-95, 2008. PMCID:2517644
· Ryzhov, S, Solenkova, NV, Goldstein, AE, Lamparter, M, Fleenor, T, Young, PP, Greelish, JP, Byrne, JG, Vaughan, DE, Biaggioni, I, Hatzopoulos, AK, Feoktistov, I. Adenosine receptor-mediated adhesion of endothelial progenitors to cardiac microvascular endothelial cells. Circ Res, 102(3), 356-63, 2008.
· Ryzhov, S, Zaynagetdinov, R, Goldstein, AE, Novitskiy, SV, Blackburn, MR, Biaggioni, I, Feoktistov, I. Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther, 324(2), 694-700, 2008.
· Ryzhov, S, Zaynagetdinov, R, Goldstein, AE, Novitskiy, SV, Dikov, MM, Blackburn, MR, Biaggioni, I, Feoktistov, I. Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J Immunol, 180(11), 7212-20, 2008.
· Ryzhov, S, McCaleb, JL, Goldstein, AE, Biaggioni, I, Feoktistov, I. Role of adenosine receptors in the regulation of angiogenic factors and neovascularization in hypoxia. J Pharmacol Exp Ther, 320(2), 565-72, 2007.
· Ryzhov, S, Goldstein, AE, Biaggioni, I, Feoktistov, I. Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. Mol Pharmacol, 70(2), 727-35, 2006.
· Feoktistov, I, Ryzhov, S, Zhong, H, Goldstein, AE, Matafonov, A, Zeng, D, Biaggioni, I. Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension, 44(5), 649-54, 2004.
· Ryzhov, S, Goldstein, AE, Matafonov, A, Zeng, D, Biaggioni, I, Feoktistov, I. Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J Immunol, 172(12), 7726-33, 2004.
· Zhong, H, Belardinelli, L, Maa, T, Feoktistov, I, Biaggioni, I, Zeng, D. A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol, 30(1), 118-25, 2004.
· Zhu, CB, Hewlett, WA, Feoktistov, I, Biaggioni, I, Blakely, RD. Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation. Mol Pharmacol, 65(6), 1462-74, 2004.
· Bshesh, K, Zhao, B, Spight, D, Biaggioni, I, Feokistov, I, Denenberg, A, Wong, HR, Shanley, TP. The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells. J Leukoc Biol, 72(5), 1027-36, 2002.
· Feoktistov, I, Goldstein, AE, Ryzhov, S, Zeng, D, Belardinelli, L, Voyno-Yasenetskaya, T, Biaggioni, I. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res, 90(5), 531-8, 2002.
· Biaggioni I, Feoktistov I . P1 receptors in the respiratory system. Handb Exp Pharmacol, 151(II), 239-279, 2001.
· Feoktistov, I, Garland, EM, Goldstein, AE, Zeng, D, Belardinelli, L, Wells, JN, Biaggioni, I. Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)(2). Biochem Pharmacol, 62(9), 1163-73, 2001.
· Grant, MB, Davis, MI, Caballero, S, Feoktistov, I, Biaggioni, I, Belardinelli, L. Proliferation, migration, and ERK activation in human retinal endothelial cells through A(2B) adenosine receptor stimulation. Invest Ophthalmol Vis Sci, 42(9), 2068-73, 2001.
· Olanrewaju, HA, Qin, W, Feoktistov, I, Scemama, JL, Mustafa, SJ. Adenosine A(2A) and A(2B) receptors in cultured human and porcine coronary artery endothelial cells. Am J Physiol Heart Circ Physiol, 279(2), H650-6, 2000.
· Audoly, LP, Ma, L, Feoktistov, I, de Foe, SK, Breyer, MD, Breyer, RM. Prostaglandin E-prostanoid-3 receptor activation of cyclic AMP response element-mediated gene transcription. J Pharmacol Exp Ther, 289(1), 140-8, 1999.
· Feoktistov, I, Goldstein, AE, Biaggioni, I. Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. Mol Pharmacol, 55(4), 726-34, 1999.
· Grant, MB, Tarnuzzer, RW, Caballero, S, Ozeck, MJ, Davis, MI, Spoerri, PE, Feoktistov, I, Biaggioni, I, Shryock, JC, Belardinelli, L. Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circ Res, 85(8), 699-706, 1999.
· Feoktistov, I, Biaggioni, I. Pharmacological characterization of adenosine A2B receptors: studies in human mast cells co-expressing A2A and A2B adenosine receptor subtypes. Biochem Pharmacol, 55(5), 627-33, 1998.
· Feoktistov, I, Biaggioni, I. Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest, 96(4), 1979-86, 1995. PMCID:185836