Differential effects of Rho-kinase inhibition on artery wall mass and remodeling.
Differential effects of Rho-kinase inhibition on artery wall mass and remodeling.
复制标题
Rho 激酶抑制对动脉壁质量和重塑的不同影响。
DOI：
10.1016/s0741-5214(03)01037-1
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发表时间：
2004
影响因子：
4.3
通讯作者：
Geary,RandolphL
中科院分区：
文献类型：
--
作者：
Pearce,JeffreyD;Li,Jing;Edwards,MatthewS;English,WilliamP;Geary,RandolphL
收缩重构和新的动脉壁质量有助于动脉粥样硬化和损伤后管腔狭窄。Rho激酶是肌球蛋白磷酸化和细胞骨架重组的重要调节因子，对平滑肌细胞（SMC）的生长和血管收缩至关重要，但其在动脉壁重塑中的作用尚不清楚。我们假设收缩性动脉壁重塑依赖于Rho信号，因此阻断Rho激酶将促进血管壁重塑以应对内膜增生，从而限制管腔narrowing.METHODSTo检验这一假设，我们首先研究了Rho激酶抑制剂法舒地尔对SMC胶原基质重塑的影响。将小鼠主动脉SMC接种到含和不含法舒地尔的三维胶原凝胶中，并在24小时时测量收缩程度。然后，我们使用小鼠颈动脉结扎模型来研究Rho激酶抑制对在体重构和内膜增生的影响。将C57 B6/J小鼠随机分配至法舒地尔（100 mg/kg/天）或溶媒组，并进行单侧颈动脉结扎或假结扎。28天后测量重塑和室壁质量。10 ~ 30 μmol/L法舒地尔可完全抑制胶原凝胶重塑。在对照组小鼠中，颈动脉结扎引起外膜、中膜和内膜显著增厚（P <0.01），颈动脉壁向外重塑。与假手术组相比，外弹性膜（EEL）面积增加了14%（P < .05），但这种增加不足以防止管腔狭窄（-42% vs假手术，P < .05）。与对照组相比，法舒地尔治疗对管壁质量有有利的影响，抑制新生内膜（P = .04）、中膜（P = .03）和外膜增厚（P = .07）。然而，与我们的假设相反，法舒地尔并没有增强外向动脉壁重塑或改善管腔口径。相反，抑制Rho-激酶阻断了对结扎反应的向外重塑。处理组动物的EEL面积显著小于对照组动物（P = 0.04），略小于假手术组动物（P = NS）。这些数据表明，Rho激活显著促进损伤动脉壁的增生和向外重塑。Rho激酶可能被证明是限制内膜增生和预防再狭窄的重要靶点，当通过其他方法（例如支架）改善重塑时。
PURPOSEConstrictive remodeling and new artery wall mass contribute to lumen narrowing in atherosclerosis and following injury. Rho-kinase, an important regulator of myosin phosphorylation and cytoskeletal reorganization, is critical to smooth muscle cell (SMC) growth and vasoconstriction, but its role in artery wall remodeling is poorly defined. We hypothesized that constrictive artery wall remodeling is dependent on Rho signaling so that blocking Rho-kinase would promote outward artery wall remodeling in response to intimal hyperplasia and thus limit lumen narrowing.METHODSTo test this hypothesis, we first studied the effects of the Rho-kinase inhibitor fasudil on SMC remodeling of collagen matrix in vitro. Mouse aortic SMCs were seeded into three-dimensional collagen gels with and without fasudil, and extent of contraction was measured at 24 hours. We then used the mouse carotid ligation model to study the effects of Rho-kinase inhibition on remodeling and intimal hyperplasia in vivo. C57B6/J mice were randomly assigned to fasudil (100 mg/kg per day) or vehicle and underwent unilateral carotid artery ligation or sham ligation. Remodeling and wall mass were measured after 28 days.RESULTSFasudil blocked SMC contraction of collagen gels in a dose-dependent manner. Complete inhibition of collagen gel remodeling was achieved between 10 and 30 μmol/L fasudil. In control mice, carotid ligation caused significant thickening of the adventitia, media, and intima (P < .01) and outward remodeling of the carotid wall. The external elastic lamina (EEL) area increased by 14% versus sham (P < .05), but this increase was insufficient to prevent lumen narrowing (−42% vs sham, P < .05). Fasudil treatment had favorable effects on wall mass, inhibiting neointimal (P = .04), medial (P = .03), and adventitial thickening (P = .07) versus controls. Opposite our hypothesis, however, fasudil did not enhance outward artery wall remodeling or improve lumen caliber. Rather, inhibiting Rho-kinase blocked outward remodeling in response to ligation. EEL area was significantly smaller in treated versus control animals (P = .04) and slightly smaller versus shams (P = NS). These data suggest that Rho activation contributes significantly to both hyperplasia and outward remodeling of the injured artery wall. Rho-kinase may prove an important target to limit intimal hyperplasia and prevent restenosis when remodeling is improved by other means (eg, stents).