Adenosine inhibits growth of human aortic smooth muscle cells via A2B receptors
Adenosine inhibits growth of human aortic smooth muscle cells via A2B receptors
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DOI：
10.1161/01.hyp.31.1.516
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发表时间：
1998-01-01
期刊：
影响因子：
8.3
通讯作者：
Jackson, EK
中科院分区：
文献类型：
--
作者：
Dubey, RK;Gillespie, DG;Jackson, EK
腺苷抑制大鼠血管平滑肌细胞（SMC）生长。然而，腺苷对人血管SMC增殖和细胞外基质蛋白（如胶原）合成的影响尚不清楚。本研究的目的是表征外源性和内源性（SMC来源）腺苷对人主动脉SMC增殖和胶原合成的影响。用2.5%的胎牛血清（FCS）刺激生长受阻的SMCs，在存在或不存在腺苷、2-氯腺苷（稳定的腺苷类似物）的情况下，以及增加内源性腺苷水平的药物，包括红-9-（2-羟基-3-壬基）腺嘌呤（EHNA）、双嘧达莫和碘tubericidin。通过DNA合成（h -3-胸苷结合）和细胞计数以及胶原合成（h -3-脯氨酸结合）评估，所有这些药物都以浓度依赖性的方式抑制了fcs诱导的SMC增殖。EHNA、双嘧达莫和碘结核菌素分别添加到SMCs时，胞外腺苷水平增加1.7 ~ 18倍，EHNA+碘结核菌素和EHNA+碘结核菌素+双嘧达莫使胞外腺苷水平增加392倍以上。KF17837（选择性A(2)拮抗剂）和DPSPX (A（1)/A(2)拮抗剂），而不是DPCPX（选择性A(1)拮抗剂），阻断了2-氯腺苷、EHNA和双嘧达末对DNA和胶原合成的抗微生物作用，表明A（2A）和/或A（2B）参与其中，但排除了A(1)受体的参与。CGS21680（选择性A（2A）激动剂）缺乏作用，排除了A（2A）受体的参与，提示A（2B）受体起主要作用。2-氯腺苷、n -6-环戊基腺苷（选择性A(1)激动剂）、NECA (A（1)/A(2)激动剂）和MECA (A（1)/A(2)激动剂）对人主动脉SMC增殖的抑制作用与A（2B）受体亚型介导腺苷对人主动脉SMC增殖的抑制作用一致。综上所述，人主动脉SMC可以合成腺苷，外源性和内源性（SMC来源的）腺苷通过激活A（2B）受体抑制SMC增殖和胶原合成。
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 (H-3-thymidine incorporation) and cell counting, as well as collagen synthesis (H-3-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 A(2) antagonist) and DPSPX (A(1)/A(2) antagonist), but not DPCPX (selective A(1) 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 A(1), 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, N-6-cyclopentyladenosine (selective A(1) agonist), NECA (A(1)/A(2) agonist), and MECA (A(1)/A(2) 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.