Ml. Peyot et al., Extracellular adenosine induces apoptosis of human arterial smooth muscle cells via A(2b)-purinoceptor, CIRCUL RES, 86(1), 2000, pp. 76-85
Apoptosis of arterial smooth muscle cells (ASMCs) could play an important r
ole in the pathogenesis of atherosclerosis and restenosis. Recent studies h
ave demonstrated that extracellular adenosine induces apoptosis in various
cell types. Our aim was to delineate the capacity of this nucleoside to ind
uce ASMC apoptosis in arterial diseases. We demonstrate that adenosine dose
-dependently triggers apoptosis of cultured human ASMCs. Apoptotic cell dea
th was quantified by analysis of nuclear chromatin morphology and character
ized 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 trans
port, dipyridamole, was able to inhibit adenosine-induced ASMC apoptosis. I
n contrast, an A(1)/A(2)-adenosine receptor antagonist, xanthine amine cong
ener, totally inhibited adenosine-induced apoptosis. Furthermore, among mor
e selective inhibitors of P-1, purinoceptor subtypes, only alloxazine, an a
ntagonist of A(1)- and A(2)-adenosine receptors, completely inhibited adeno
sine-induced ASMC apoptosis, suggesting that adenosine triggers ASMC apopto
sis via either 1 or both of these receptors. However, 8-cyclopentyl-1,3-dip
ropylxanthine, 8-(3-chlorostyryl) caffeine, and 3-ethyl-5-benzyl-2-methyl-4
phenylethynyl-6-phenyl- 1,4-(+/-)-dihydropyridine-3,5-dicarboxylate, which
are A(1)-, A(2n)-, and A(3)-adenosine receptor antagonists, did not inhibit
adenosine-induced apoptosis, suggesting an involvement of the A(2b)-recept
or in this process. Moreover, the cAMP increase followed by cAMP-dependent
protein kinase activation appears essential to mediate adenosine-induced AS
MC apoptosis, thus confirming the previous hypothesis. These results indica
te that adenosine-induced apoptosis of ASMCs is essentially mediated via A(
2b)-adenosine receptor and involves a cAMP-dependent pathway.