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Antiproliferative effects of A02011‐1, an adenylyl cyclase activator, in cultured vascular smooth muscle cells of rat
Author(s) -
Yu SheuMeei,
Cheng ZhiJiao,
Kuo ShengChu
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13337.x
Subject(s) - adenylyl cyclase , forskolin , ibmx , adenosine , medicine , endocrinology , vascular smooth muscle , phosphodiesterase , phosphodiesterase inhibitor , protein kinase a , staurosporine , adcy9 , activator (genetics) , cyclic nucleotide phosphodiesterase , dna synthesis , adcy10 , biology , cyclic adenosine monophosphate , chemistry , biochemistry , kinase , enzyme , stimulation , receptor , in vitro , smooth muscle
1 The effects of A02011‐1, a pyrazole derivative, on the proliferation of rat vascular smooth muscle cells (VSMCs) were examined. 2 A02011‐1 (1–100 μ m ) concentration‐dependently inhibited [ 3 H]‐thymidine incorporation into DNA in rat VSMCs that were synchronized by 48 h serum depletion and then re‐stimulated by addition of foetal calf serum (FCS, 10%), platelet‐derived growth factor (PDGF, 10 ng ml −1 ), 5‐hydroxytryptamine (10 μ m ) or ADP (10 μ m ). The inhibitory effect of A02011‐1 was fully reversible. However, FCS‐induced [ 3 H]‐thymidine incorporation into rat endothelial cells was unaffected by A02011‐1. 3 The concentration of A02011‐1 necessary for inhibition of the FCS‐induced proliferation was similar to that necessary for adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) formation. Adenylyl cyclase activity was increased in A02011‐1‐treated VSMCs, whereas cyclic AMP‐specific phosphodiesterase activity was unchanged. 4 A02011‐1 was equipotent with forskolin but was more potent than 8‐bromo‐cyclic AMP against FCS (10%)‐induced proliferation. 5 The antiproliferative action of A02011‐1 was mimicked by 8‐bromo‐cyclic AMP, a membrane‐permeable cyclic AMP analogue and was antagonized by 2′,5′‐dideoxyadenosine, an adenylyl cyclase inhibitor and by Rp‐cyclic AMPS, a competitive inhibitor of cyclic AMP‐dependent protein kinase (PKA) type I and II. 3‐Isobutyl‐1‐methylxanthine (IBMX) caused significant potentiation of the antiproliferative activity of A02011‐1. However, Rp‐8‐bromo‐cyclic GMPS and staurosporine did not affect the antiproliferative activity of A02011‐1. 6 A02011‐1 still inhibited the FCS‐induced DNA synthesis even when added 10–18 h after re‐stimulation of the serum‐starved VSMCs with 10% FCS. Flow cytometry in synchronized cells revealed an acute blockade of FCS‐inducible cell cycle progression at a point in the G 1 /S phase in A02011‐1‐treated cells. The inhibition of proliferation by A02011‐1 was shown to be independent of cell damage, as documented by several criteria of cell viability. 7 These results indicate that A02011‐1 inhibition of VSMC proliferation was mediated by cyclic AMP and was due to a delay in the progression from the G 1 into S phase of the cell cycle. A02011‐1 did not cause cell toxicity and may thus hold promising potential for the prevention of atherosclerosis or vascular diseases.