Myllärniemi M, Calderon L, Lemström K, Buchdunger E, Häyry P
Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Finland.
FASEB J. 1997 Nov;11(13):1119-26. doi: 10.1096/fasebj.11.13.9367346.
Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been linked to vascular smooth muscle cell (SMC) migration and proliferation leading to atherosclerosis, restenosis, and chronic allograft rejection. This study describes the effect of CGP 53716, a specific PDGFR tyrosine kinase inhibitor on SMC proliferation and migration in vitro and in neointimal formation in vivo. CGP 53716 inhibited dose dependently tyrosine phosphorylation of both the known PDGFRs: the PDGFR-alpha and PDGFR-beta. In primary rat SMC cultures, a dose-dependent inhibition of PDGF-AA and PDGF-BB induced migration, and tritiated thymidine incorporation of SMC was seen at nontoxic concentrations. After rat carotid artery ballooning injury in vivo, the migration of alpha-actin-positive cells on the luminal side of internal elastic lamina was decreased with 50 mg x kg(-1) x day(-1) of CGP 53716 from 38 +/- 10 (control group) to 4 +/- 2 (P<0.0001, Mann-Whitney U test, N=18). CGP 53716 did not inhibit the number of replicating bromodeoxyuridine (BrdU)-incorporating cells in the intima, media, or adventitia during BrdU labeling at 0-96 postoperative h, though it inhibited significantly (P<0.01) the replication of medial and intimal cells from 93 h onward. Intima/media ratio was inhibited by 40% after 14 days in the CGP 53716-treated group (P=0.028) after rat aortic denudation. The results indicate that inhibition of the PDGFR tyrosine kinase inhibits SMC migration and proliferation in vitro, SMC migration, and, to a lesser extent, proliferation after ballooning injury in vivo, confirming a causal role for activation of the PDGFR and the formation of neointimal lesions.
血小板衍生生长因子（PDGFs）及其受体（PDGFRs）与血管平滑肌细胞（SMC）的迁移和增殖有关，可导致动脉粥样硬化、再狭窄和慢性同种异体移植排斥反应。本研究描述了特异性PDGFR酪氨酸激酶抑制剂CGP 53716对体外SMC增殖和迁移以及体内新生内膜形成的影响。CGP 53716剂量依赖性地抑制已知的两种PDGFRs（PDGFR-α和PDGFR-β）的酪氨酸磷酸化。在原代大鼠SMC培养物中，在无毒浓度下可见对PDGF-AA和PDGF-BB诱导的迁移以及SMC的氚化胸腺嘧啶核苷掺入的剂量依赖性抑制。在大鼠体内颈动脉球囊损伤后，给予50 mg·kg⁻¹·d⁻¹的CGP 53716，内弹力膜腔面α-肌动蛋白阳性细胞的迁移从38±10（对照组）降至4±2（P<0.0001，Mann-Whitney U检验，N = 18）。在术后0 - 96小时的BrdU标记期间，CGP 53716并未抑制内膜、中膜或外膜中掺入BrdU的复制细胞数量，尽管从93小时起它显著抑制（P<0.01）中膜和内膜细胞的复制。在大鼠主动脉剥脱术后14天，CGP 53716治疗组的内膜/中膜比值被抑制了40%（P = 0.028）。结果表明，抑制PDGFR酪氨酸激酶可抑制体外SMC迁移和增殖、体内球囊损伤后的SMC迁移以及程度较轻的增殖，证实了PDGFR激活与新生内膜病变形成之间的因果关系。
