Numaguchi Y, Naruse K, Harada M, Osanai H, Mokuno S, Murase K, Matsui H, Toki Y, Ito T, Okumura K, Hayakawa T
Department of Internal Medicine II, and Physiology, Nagoya University School of Medicine, Nagoya University School of Health Science, Nagoya, Japan.
Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):727-33. doi: 10.1161/01.atv.19.3.727.
Prostacyclin (PGI2), a metabolite of arachidonic acid, has the vasoprotective effects of vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. We hypothesized that an overexpression of endogenous PGI2 may accelerate the recovery from endothelial damage and inhibit neointimal formation in the injured artery. To test this hypothesis, we investigated in vivo transfer of the PGI2 synthase (PCS) gene into balloon-injured rat carotid arteries by a nonviral lipotransfection method. Seven days after transfection, a significant regeneration of endothelium was observed in the arteries transfected with a plasmid carrying the rat PCS gene (pCMV-PCS), but little regeneration was seen in those with the control plasmid carrying the lacZ gene (pCMV-lacZ) (percent luminal circumference lined by newly regenerated endothelium: 87. 1+/-6.9% in pCMV-PCS-transfected vessels and 6.9+/-0.2% in pCMV-lacZ vessels, P<0.001). BrdU staining of arterial segments demonstrated a significantly lower incorporation in pCMV-PCS-transfected vessels (7. 5+/-0.3% positive nuclei in vessel cells) than in pCMV-lacZ (50. 7+/-9.6%, P<0.01). Moreover, 2 weeks after transfection, the PCS gene transfer resulted in a significant inhibition of neointimal formation (88% reduction in ratio of intima/media areas), whereas medial area was similar among the groups. Arterial segments transfected with pCMV-PCS produced significantly higher levels of 6-keto-PGF1alpha, the main metabolite of PGI2, compared with the segments transfected with pCMV-lacZ (10.2+/-0.55 and 2.1+/-0.32 ng/mg tissue for pCMV-PCS and pCMV-placZ, P<0.001). In conclusion, this study demonstrated that an in vivo PCS gene transfer increased the production of PGI2 and markedly inhibited neointimal formation with accelerated reendothelialization in rat carotid arteries after balloon injury.
前列环素（PGI2）是花生四烯酸的代谢产物，具有血管舒张、抗血小板聚集和平滑肌细胞增殖抑制等血管保护作用。我们推测内源性PGI2的过表达可能会加速内皮损伤的恢复，并抑制受损动脉的新生内膜形成。为了验证这一假设，我们采用非病毒脂质转染方法研究了PGI2合酶（PCS）基因在体内向球囊损伤的大鼠颈动脉的转移情况。转染7天后，在转染携带大鼠PCS基因的质粒（pCMV-PCS）的动脉中观察到内皮细胞的显著再生，而在转染携带lacZ基因的对照质粒（pCMV-lacZ）的动脉中几乎未见再生（新生内皮细胞覆盖的管腔周长百分比：pCMV-PCS转染血管为87.1±6.9%，pCMV-lacZ血管为6.9±0.2%，P<0.001）。动脉段的BrdU染色显示，pCMV-PCS转染血管中的掺入率（血管细胞中阳性细胞核占7.5±0.3%）显著低于pCMV-lacZ（50.7±9.6%，P<0.01）。此外，转染2周后，PCS基因转移导致新生内膜形成受到显著抑制（内膜/中膜面积比值降低88%），而各组之间的中膜面积相似。与转染pCMV-lacZ的动脉段相比，转染pCMV-PCS的动脉段产生的PGI2主要代谢产物6-酮-PGF1α水平显著更高（pCMV-PCS和pCMV-placZ分别为10.2±0.55和2.1±0.32 ng/mg组织，P<0.001）。总之，本研究表明，体内PCS基因转移增加了PGI2的产生，并显著抑制了大鼠颈动脉球囊损伤后的新生内膜形成，同时加速了内皮再内皮化。
