Mooradian D L, Fernandes B, Diglio C A, Lester B R
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
J Cardiovasc Pharmacol. 1995 Apr;25(4):611-8. doi: 10.1097/00005344-199504000-00015.
Angiopeptin (AP: BIM23014C), a cyclic analogue of the peptide hormone somatostatin, inhibits intimal hyperplasia after balloon angioplasty. This inhibition has been attributed to a direct inhibitory effect on smooth muscle cell (SMC) proliferation. However, the SMC that proliferate in the intima and contribute to intimal hyperplasia arrive there by migrating from the injured media, suggesting that SMC migration may also play an important role in this process. Indeed, in the experiments we describe, AP inhibited the migration of rat aortic SMC cells (RA-SMC) in response to type I collagen, the predominant form of collagen in the vessel media, and did so dose dependently. RA-SMC migration was inhibited 70% in the presence of AP 100 nM. RA-SMC adhesion to type I collagen in these conditions was not inhibited, suggesting that AP does not interfere with RA-SMC recognition of type I collagen; instead, it blocks subsequent signaling events that are necessary for RA-SMC migration in response to type I collagen. AP inhibited the forskolin-stimulated accumulation of cyclic AMP by RA-SMC (35% at 30 nM). In addition, pertussis toxin (PT), which blocks Gi-mediated inhibition of adenylyl cyclase, blocked the inhibitory effect of AP on cyclic AMP (cAMP) accumulation and also blocked the inhibitory effect of AP on RA-SMC migration. These findings suggest that the inhibitory effect of AP on intimal hyperplasia is due at least in part to its effects on SMC migration and that these effects are mediated by a Gi-dependent pathway and may involve inhibition of adenylyl cyclase and cAMP accumulation.
血管肽素（AP：BIM23014C）是肽激素生长抑素的环状类似物，可抑制球囊血管成形术后的内膜增生。这种抑制作用归因于对平滑肌细胞（SMC）增殖的直接抑制作用。然而，在内膜中增殖并导致内膜增生的SMC是从受损的中膜迁移而来的，这表明SMC迁移在这一过程中也可能起重要作用。事实上，在我们所描述的实验中，AP抑制了大鼠主动脉SMC细胞（RA-SMC）对I型胶原（血管中膜中主要的胶原形式）的迁移反应，且呈剂量依赖性。在存在100 nM AP的情况下，RA-SMC迁移受到70%的抑制。在这些条件下，RA-SMC对I型胶原的黏附未受抑制，这表明AP不会干扰RA-SMC对I型胶原的识别；相反，它阻断了RA-SMC对I型胶原迁移所必需的后续信号事件。AP抑制了福斯高林刺激的RA-SMC中环状AMP的积累（30 nM时为35%）。此外，百日咳毒素（PT）可阻断Gi介导的腺苷酸环化酶抑制作用，它阻断了AP对环状AMP（cAMP）积累的抑制作用，也阻断了AP对RA-SMC迁移的抑制作用。这些发现表明，AP对内膜增生的抑制作用至少部分归因于其对SMC迁移的影响，且这些影响是由Gi依赖性途径介导的，可能涉及腺苷酸环化酶和cAMP积累的抑制。
