Matsuno Hiroyuki, Takei Mariko, Hayashi Hideharu, Nakajima Keiichi, Ishisaki Akira, Kozawa Osamu
Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan.
J Cardiovasc Pharmacol. 2004 Mar;43(3):333-40. doi: 10.1097/00005344-200403000-00002.
The search for a novel therapy for endothelial regenerating is an area of intensive investigation. Recent experimental and clinical evidence strongly suggests that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have several physiological effects independent of low-density lipoprotein cholesterol reduction. We here report that the carotid arterial blood flow after endothelial injury in hamsters treated with simvastatin was restored, in contrast to the situation in nontreated hamsters. Histologic observations showed a prompt recovery of endothelial cells with a much higher DNA synthesis index in repaired endothelium of hamsters treated with simvastatin. The amount of secreted vascular endothelial cell growth factor (VEGF) by cultured vascular smooth muscle cells from hamsters treated with simvastatin was significantly increased. Mevalonate reduced the amount of VEGF secretion by simvastatin in vitro. Finally, an injection of either an anti-VEGF antibody or an anti-VEGF receptor-1 (Flt-1) antibody, but not anti-VEGF receptor-2 (Flk-1), reduced the prompt endothelial healing. Simvastatin regulates endothelial regenerating by an over-release of VEGF and by this may result in prompt endothelial healing after vascular injury. Our results provide new insights into the role of statin and VEGF in the pathogenesis of vascular diseases.
寻找一种用于内皮再生的新型疗法是一个深入研究的领域。最近的实验和临床证据有力地表明，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）具有多种独立于降低低密度脂蛋白胆固醇的生理效应。我们在此报告，与未治疗的仓鼠相比，用辛伐他汀治疗的仓鼠在内皮损伤后的颈动脉血流得以恢复。组织学观察显示，在用辛伐他汀治疗的仓鼠修复的内皮中，内皮细胞迅速恢复，DNA合成指数高得多。用辛伐他汀治疗的仓鼠培养的血管平滑肌细胞分泌的血管内皮细胞生长因子（VEGF）量显著增加。甲羟戊酸在体外降低了辛伐他汀诱导的VEGF分泌量。最后，注射抗VEGF抗体或抗VEGF受体-1（Flt-1）抗体，但不注射抗VEGF受体-2（Flk-1）抗体，可减少内皮的迅速愈合。辛伐他汀通过过度释放VEGF来调节内皮再生，由此可能导致血管损伤后内皮的迅速愈合。我们的结果为他汀类药物和VEGF在血管疾病发病机制中的作用提供了新的见解。
