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(Circulation Research. 2000;86:76.)
© 2000 American Heart Association, Inc.

Cellular Biology

Extracellular Adenosine Induces Apoptosis of Human Arterial Smooth Muscle Cells via A_2b-Purinoceptor

Marie-Line Peyot, Alain-Pierre Gadeau, Frédéric Dandré, Isabelle Belloc, Françoise Dupuch, Claude Desgranges

From the Unité INSERM 441, Pessac, France.

Correspondence to Dr Claude Desgranges, Unité INSERM 441, avenue du Haut-Lévêque, 33600 Pessac, France. E-mail claude.desgranges{at}bordeaux.inserm.fr

Abstract—Apoptosis of arterial smooth muscle cells (ASMCs) could play an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have demonstrated that extracellular adenosine induces apoptosis in various cell types. Our aim was to delineate the capacity of this nucleoside to induce ASMC apoptosis in arterial diseases. We demonstrate that adenosine dose-dependently triggers apoptosis of cultured human ASMCs. Apoptotic cell death was quantified by analysis of nuclear chromatin morphology and characterized by DNA laddering. The involvement of adenosine receptors was suggested, because neither an adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, nor an inhibitor of cellular nucleoside transport, dipyridamole, was able to inhibit adenosine-induced ASMC apoptosis. In contrast, an A₁/A₂-adenosine receptor antagonist, xanthine amine congener, totally inhibited adenosine-induced apoptosis. Furthermore, among more selective inhibitors of P₁ purinoceptor subtypes, only alloxazine, an antagonist of A₁- and A₂-adenosine receptors, completely inhibited adenosine-induced ASMC apoptosis, suggesting that adenosine triggers ASMC apoptosis via either 1 or both of these receptors. However, 8-cyclopentyl-1,3-dipropylxanthine, 8-(3-chlorostyryl) caffeine, and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate, which are A₁-, A_2a-, and A₃-adenosine receptor antagonists, did not inhibit adenosine-induced apoptosis, suggesting an involvement of the A_2b-receptor in this process. Moreover, the cAMP increase followed by cAMP-dependent protein kinase activation appears essential to mediate adenosine-induced ASMC apoptosis, thus confirming the previous hypothesis. These results indicate that adenosine-induced apoptosis of ASMCs is essentially mediated via A_2b-adenosine receptor and involves a cAMP-dependent pathway.

Key Words: apoptosis • adenosine • arterial smooth muscle cell • A_2b purinoceptor • cAMP

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