Wong J, Rauhöft C, Dilley R J, Agrotis A, Jennings G L, Bobik A
Cell Biology Laboratory, Baker Medical Research Institute and Alfred Hospital, Victoria, Australia.
Circulation. 1997 Sep 2;96(5):1631-40. doi: 10.1161/01.cir.96.5.1631.
ACE inhibitors can attenuate the development of intimal fibrocellular lesions after balloon catheter vessel injury, but the mechanisms responsible are unknown.
To evaluate how basic fibroblast growth factor (FGF-2) and the platelet-derived growth factor (PDGF) isoforms are affected by ACE inhibition in injured rat carotid arteries in relation to smooth muscle cell (SMC) proliferation, we examined the effects of oral perindopril on FGF-2 and PDGF isoform levels in carotid arteries 2 days after balloon catheter injury. [3H]Thymidine incorporation into medial and intimal SMCs was also assessed. Uninjured vessels contained two forms of FGF-2, with molecular weights of 18 and 22 kD, and PDGF-AA. Two days after injury, FGF-2 and PDGF-AA levels were markedly reduced, but high levels of PDGF-AB became apparent when the SMCs were proliferating. Perindopril completely abolished the biosynthesis of PDGF-AB but had little effect on residual FGF-2. This was accompanied by a 25% reduction in medial SMC proliferation. Neointimal cell proliferation 10 days after injury was unaffected by perindopril, although neointima size was reduced by 30%. Commencing perindopril treatment 4 days after the injury confirmed that early events associated with effects on medial SMCs were the major contributors to the attenuated neointimal lesions.
The ability of ACE inhibitors such as perindopril to attenuate neointima formation and growth in balloon catheter-injured rat carotid arteries is dependent on early events in the media, the inhibition of SMC PDGF-AB biosynthesis and attenuation of proliferation. Neointima formation in similarly injured vessels containing SMCs that are either unresponsive to PDGF-AB or exhibit an ACE-independent profile of growth factor biosynthesis responses may account for the ineffectiveness of ACE inhibition in some species.
血管紧张素转换酶（ACE）抑制剂可减轻球囊导管血管损伤后内膜纤维细胞性病变的发展，但其作用机制尚不清楚。
为了评估在损伤的大鼠颈动脉中，碱性成纤维细胞生长因子（FGF-2）和血小板衍生生长因子（PDGF）异构体如何受ACE抑制影响以及与平滑肌细胞（SMC）增殖的关系，我们检测了口服培哚普利对球囊导管损伤后2天大鼠颈动脉中FGF-2和PDGF异构体水平的影响。还评估了[3H]胸腺嘧啶核苷掺入中膜和内膜SMC的情况。未损伤的血管含有两种形式的FGF-2，分子量分别为18和22 kD，以及PDGF-AA。损伤后2天，FGF-2和PDGF-AA水平显著降低，但当SMC增殖时，高水平的PDGF-AB变得明显。培哚普利完全抑制了PDGF-AB的生物合成，但对残余的FGF-2影响很小。这伴随着中膜SMC增殖减少25%。损伤后10天的新生内膜细胞增殖不受培哚普利影响，尽管新生内膜大小减少了30%。损伤后4天开始使用培哚普利治疗证实，与对中膜SMC的作用相关的早期事件是新生内膜病变减轻的主要原因。
培哚普利等ACE抑制剂减轻球囊导管损伤的大鼠颈动脉新生内膜形成和生长的能力取决于中膜早期事件、对SMC的PDGF-AB生物合成的抑制以及增殖的减轻。在含有对PDGF-AB无反应或表现出ACE非依赖性生长因子生物合成反应特征的SMC的类似损伤血管中，新生内膜形成可能解释了ACE抑制在某些物种中无效的原因。
