This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dubey, R. K. Articles by Jackson, E. K. Search for Related Content PubMed PubMed Citation Articles by Dubey, R. K. Articles by Jackson, E. K.

(Hypertension. 1998;31:516.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Adenosine Inhibits Growth of Human Aortic Smooth Muscle Cells Via A_2B Receptors

Raghvendra K. Dubey; Delbert G. Gillespie; Zaichuan Mi; Edwin K. Jackson

From Center for Clinical Pharmacology, Departments of Medicine (R.K.D., D.G.G., Z.M.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, USA

Correspondence to Dr. Raghvendra K. Dubey, Center for Clinical Pharmacology, Department of Medicine 623 Scaife Hall, 200 Lothrop Street, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582. E-Mail: dubey{at}novell2.dept-med.pitt.edu

Adenosine inhibits rat vascular smooth muscle cell (SMC) growth. However, the effects of adenosine on human vascular SMC proliferation and synthesis of extracellular matrix proteins, such as collagen, are unknown. The objective of this study was to characterize the effects of exogenous and endogenous (SMC-derived) adenosine on human aortic SMC proliferation and collagen synthesis. Growth-arrested SMCs were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), and with agents that increase endogenous adenosine levels, including erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), dipyridamole, and iodotubericidin. All of these agents inhibited in a concentration-dependent manner FCS-induced SMC proliferation as assessed by DNA synthesis (³H-thymidine incorporation) and cell counting, as well as collagen synthesis (³H-proline incorporation). EHNA, dipyridamole, and iodotubericidin increased extracellular levels of adenosine by 1.7-fold to 18-fold when added separately to SMCs, and EHNA+iodotubericidin and EHNA+iodotubericidin+dipyridamole increased extracellular adenosine levels by more than 392-fold. Both KF17837 (selective A₂ antagonist) and DPSPX (A₁/A₂ antagonist), but not DPCPX (selective A₁ antagonist), blocked the antimitogenic effects of 2-chloroadenosine, EHNA, and dipyridamole on DNA and collagen synthesis, suggesting the involvement of A_2A and/or A_2B, but excluding the participation of A₁, receptors. The lack of effect of CGS21680 (selective A_2A agonist), excluded involvement of A_2A receptors and suggested a major role for A_2B receptors. A comparison of the inhibitory potencies of 2-chloroadenosine, N⁶-cyclopentyladenosine (selective A₁ agonist), NECA (A₁/A₂ agonist), and MECA (A₁/A₂ agonist) were consistent with an A_2B receptor subtype mediating the inhibitory effects of adenosine on human aortic SMC proliferation. In conclusion, human aortic SMCs synthesize adenosine, and exogenous as well as endogenous (SMC-derived) adenosine inhibits SMC proliferation and collagen synthesis via activation of A_2B receptors.

Key Words: adenosine • smooth muscle cells • hypertension • atherosclerosis • restenosis • proliferation • hyperplasia • extracellular matrix • collagen

Abbreviations: DMEM = Dulbecco’s Modified Eagle Medium • ECM = extracellular matrix • FCS = fetal calf serum • HBSS = Hanks’ balanced salt solution • HASMCs = human aortic SMCs • PBS = phosphate buffered saline • SMC = smooth muscle cell

This article has been cited by other articles:

				B. S. Dixon, G. J. Beck, M. A. Vazquez, A. Greenberg, J. A. Delmez, M. Allon, L. M. Dember, J. Himmelfarb, J. J. Gassman, T. Greene, et al. Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency N. Engl. J. Med., May 21, 2009; 360(21): 2191 - 2201. [Abstract] [Full Text] [PDF]

				D. Yang, M. Koupenova, D. J. McCrann, K. J. Kopeikina, H. M. Kagan, B. M. Schreiber, and K. Ravid The A2b adenosine receptor protects against vascular injury PNAS, January 15, 2008; 105(2): 792 - 796. [Abstract] [Full Text] [PDF]

				E. K. Jackson, Z. Mi, and R. K. Dubey The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 117 - 123. [Abstract] [Full Text] [PDF]

				X. Yang, D. P. Thomas, X. Zhang, B. W. Culver, B. M. Alexander, W. J. Murdoch, M. N.A. Rao, D. A. Tulis, J. Ren, and N. Sreejayan Curcumin Inhibits Platelet-Derived Growth Factor-Stimulated Vascular Smooth Muscle Cell Function and Injury-Induced Neointima Formation Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 85 - 90. [Abstract] [Full Text] [PDF]

				D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3553 - 3562. [Abstract] [Full Text] [PDF]

				G. P. H. Leung, R. Y. K. Man, and C.-M. Tse D-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2756 - H2762. [Abstract] [Full Text] [PDF]

				J. Shen, S. P. Halenda, M. Sturek, and P. A. Wilden Novel Mitogenic Effect of Adenosine on Coronary Artery Smooth Muscle Cells: Role for the A1 Adenosine Receptor Circ. Res., May 13, 2005; 96(9): 982 - 990. [Abstract] [Full Text] [PDF]

				T. Pawelczyk, M. Podgorska, and M. Sakowicz The Effect of Insulin on Expression Level of Nucleoside Transporters in Diabetic Rats Mol. Pharmacol., January 1, 2003; 63(1): 81 - 88. [Abstract] [Full Text] [PDF]

				J. D. Ahn, R. Morishita, Y. Kaneda, S.-J. Lee, K.-Y. Kwon, S.-Y. Choi, K.-U. Lee, J.-Y. Park, I.-J. Moon, J.-G. Park, et al. Inhibitory Effects of Novel AP-1 Decoy Oligodeoxynucleotides on Vascular Smooth Muscle Cell Proliferation In Vitro and Neointimal Formation In Vivo Circ. Res., June 28, 2002; 90(12): 1325 - 1332. [Abstract] [Full Text] [PDF]

				G. Burnstock Purinergic Signaling and Vascular Cell Proliferation and Death Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 364 - 373. [Abstract] [Full Text] [PDF]

				B. B. Fredholm, A. P. IJzerman, K. A. Jacobson, K.-N. Klotz, and J. Linden International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors Pharmacol. Rev., December 1, 2001; 53(4): 527 - 552. [Abstract] [Full Text] [PDF]

				E. K. Jackson and R. K. Dubey Role of the extracellular cAMP-adenosine pathway in renal physiology Am J Physiol Renal Physiol, October 1, 2001; 281(4): F597 - F612. [Abstract] [Full Text] [PDF]

				S. J. Mundell, M. E. Olah, R. A. Panettieri Jr., J. L. Benovic, and R. B. Penn Regulation of G Protein-Coupled Receptor-Adenylyl Cyclase Responsiveness in Human Airway Smooth Muscle by Exogenous and Autocrine Adenosine Am. J. Respir. Cell Mol. Biol., February 1, 2001; 24(2): 155 - 163. [Abstract] [Full Text]

				T. TAKEZAKO, K. NODA, E. TSUJI, M. KOGA, M. SASAGURI, and K. ARAKAWA Adenosine Activates Aromatic L-Amino Acid Decarboxylase Activity in the Kidney and Increases Dopamine J. Am. Soc. Nephrol., January 1, 2001; 12(1): 29 - 36. [Abstract] [Full Text]

				S. Mattig and A. Deussen Significance of adenosine metabolism of coronary smooth muscle cells Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H117 - H124. [Abstract] [Full Text] [PDF]

				J.-W. Gu, B. R. Ito, A. Sartin, N. Frascogna, M. Moore, and T. H. Adair Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2116 - H2123. [Abstract] [Full Text] [PDF]

				L. J. Rubin, L. R. Johnson, J. R. Dodam, A. K. Dhalla, L. Magliola, M. H. Laughlin, and A. W. Jones Selective transport of adenosine into porcine coronary smooth muscle Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1397 - H1410. [Abstract] [Full Text] [PDF]

				B. T. Andresen, D. G. Gillespie, Z. Mi, R. K. Dubey, and E. K. Jackson Role of Adenosine A1 Receptors in Modulating Extracellular Adenosine Levels J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 76 - 80. [Abstract] [Full Text]

				A. Y. Saadjian, F. Paganelli, M. L. Reynaud Gaubert, S. Levy, and R. P. Guieu Adenosine plasma concentration in pulmonary hypertension Cardiovasc Res, July 1, 1999; 43(1): 228 - 236. [Abstract] [Full Text] [PDF]

				J. A. Auchampach and R. Bolli Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1113 - H1116. [Full Text] [PDF]

				R. K. Dubey, D. G. Gillespie, and E. K. Jackson Adenosine Inhibits Collagen and Total Protein Synthesis in Vascular Smooth Muscle Cells Hypertension, January 1, 1999; 33(1): 190 - 194. [Abstract] [Full Text] [PDF]

				R. K. Dubey, D. G. Gillespie, and E. K. Jackson Adenosine Inhibits Collagen and Protein Synthesis in Cardiac Fibroblasts : Role of A2B Receptors Hypertension, April 1, 1998; 31(4): 943 - 948. [Abstract] [Full Text] [PDF]