Kozai Toshiyuki, Eto Masato, Yang Zhihong, Shimokawa Hiroaki, Lüscher Thomas F
Cardiology, Cardiovascular Center, University Hospital, CH-8091 Zürich, Switzerland.
Cardiovasc Res. 2005 Dec 1;68(3):475-82. doi: 10.1016/j.cardiores.2005.07.002. Epub 2005 Aug 11.
Pulsatile forces regulate vascular remodeling and trigger vascular diseases such as saphenous vein graft disease. The saphenous vein is exposed to high pressure and pulsatility only after implantation. Statins have been proved to reduce the incidence of vein graft failure. Thus, we investigated the molecular mechanisms of pulsatile stretch-induced saphenous vein smooth muscle cell (SMC) proliferation and potential beneficial effects of statins.
Human saphenous vein SMCs were subjected to cyclic stretch (60 cycles/min) in Flex I plates. Cerivastatin and simvastatin significantly prevented stretch-induced increase in SMC proliferation. Stretch induced the membrane accumulation of Rho A and Rho kinase inhibitors (Y-27632 and hydroxyfasudil) and dominant negative Rho A mutant significantly prevented stretch-induced SMC proliferation. In addition, stretch increased the levels of both p44/42 mitogen-activated protein (MAP) kinase and Akt phosphorylation. MAP kinase kinase (MEK)1/2 inhibitor U0126, phosphatidylinositol (PI) 3-kinase inhibitors (wortmannin and LY294002), and dominant negative Akt mutant significantly prevented stretch-induced SMC proliferation. Cerivastatin significantly prevented stretch-induced membrane accumulation of Rho A. On the other hand, stretch-induced phosphorylation of p44/42 MAP kinase and Akt was not prevented by cerivastatin. Mevalonate restored the preventive effect of cerivasatain on stretch-induced Rho A membrane accumulation. Stretch induced hyperphosphorylation of retinoblastoma protein (pRb), which was prevented by cerivastatin and the Rho kinase inhibitors.
Statins prevent stretch-induced saphenous vein SMC proliferation via inhibition of the Rho/Rho-kinase pathway. This may explain the beneficial effects of this class of drug, especially for patients after coronary artery bypass grafting.
搏动性力量调节血管重塑并引发诸如大隐静脉移植血管病变等血管疾病。大隐静脉仅在植入后才会受到高压和搏动性影响。他汀类药物已被证明可降低静脉移植血管失败的发生率。因此，我们研究了搏动性牵张诱导大隐静脉平滑肌细胞（SMC）增殖的分子机制以及他汀类药物的潜在有益作用。
将人源大隐静脉SMC置于Flex I板中进行循环牵张（60次/分钟）。西立伐他汀和辛伐他汀显著阻止了牵张诱导的SMC增殖增加。牵张诱导Rho A和Rho激酶抑制剂（Y-27632和羟基法舒地尔）在细胞膜上的积聚，显性阴性Rho A突变体显著阻止了牵张诱导的SMC增殖。此外，牵张增加了p44/42丝裂原活化蛋白（MAP）激酶和Akt磷酸化水平。MAP激酶激酶（MEK）1/2抑制剂U0126、磷脂酰肌醇（PI）3激酶抑制剂（渥曼青霉素和LY294002）以及显性阴性Akt突变体显著阻止了牵张诱导的SMC增殖。西立伐他汀显著阻止了牵张诱导的Rho A在细胞膜上的积聚。另一方面，西立伐他汀并未阻止牵张诱导的p44/42 MAP激酶和Akt的磷酸化。甲羟戊酸恢复了西立伐他汀对牵张诱导的Rho A细胞膜积聚的预防作用。牵张诱导视网膜母细胞瘤蛋白（pRb）的过度磷酸化，这被西立伐他汀和Rho激酶抑制剂所阻止。
他汀类药物通过抑制Rho/Rho激酶途径阻止牵张诱导的大隐静脉SMC增殖。这可能解释了这类药物的有益作用，特别是对于冠状动脉旁路移植术后的患者。
