Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury
Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury
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DOI：
10.1038/nm0797-775
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发表时间：
1997-07-01
期刊：
影响因子：
82.9
通讯作者：
Chiarello, M
中科院分区：
文献类型：
--
作者：
Indolfi, C;Avvedimento, EV;Chiarello, M
动脉壁损伤诱导新生内膜的形成(1)。这种结构是由有丝分裂激活的动脉壁平滑肌细胞生长产生的（2-5）。新内膜形成的分子机制涉及细胞生长失控，主要由动脉壁损伤引发（6-9）。传递损伤诱导的有丝分裂刺激的活化基因产物已被确定并通过几种手段加以抑制：跨显性阴性表达载体、反义寡脱氧核苷酸、腺病毒介导的基因转移、抗体和灭活药物（8,10-12）。我们的研究结果表明，大鼠局部给予3',5'-环AMP和磷酸二酯酶抑制剂（氨茶碱和氨啡酮）在体内和体外平滑肌细胞中明显抑制球囊损伤后新内膜的形成。氨茶碱的生长抑制作用被camp依赖性蛋白激酶A （PKA）的抑制完全逆转。这些发现提示了治疗与损伤诱导的动脉壁细胞生长相关的疾病的另一种方法，因为在临床环境中刺激cAMP信号在药理学上是可行的。
Injury of the arterial wall induces the formation of the neointima(1). This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall(2-5). The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall(6-9). The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs(8,10-12). Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.