Liu Ban, Zhang Jian-Ying, Cao Hua-Ming, Wang Qiang, Wang Hong-Bao
Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, China.
Intern Med. 2012;51(10):1177-82. doi: 10.2169/internalmedicine.51.6771. Epub 2012 May 15.
HMG-CoA reductase inhibitors (statins) inhibit cholesterol biosynthesis, and also decrease the formation of isoprenoid intermediates required for the activation of Rho kinase (ROCK) pathway. ROCK pathway plays pivotal roles in cardiovascular diseases including arteriosclerosis. It has been implicated that inhibition of ROCK can reverse vascular dysfunction in humans with atherosclerosis. However, it is not clear whether statins, at doses used to lower cholesterol levels, inhibit ROCK activity in humans with atherosclerosis.
We treated 40 subjects with stable atherosclerosis with rosuvastatin 10 mg/day, or rosuvastatin 40 mg/day for 28 days in a randomized, double-blinded study. We assessed the change in the lipid levels, C-reactive protein (CRP), ROCK activity, and flow-mediated dilation (FMD) of the brachial artery before and after statins therapy.
Treatment with rosuvastatin 10 mg and 40 mg significantly reduced LDL cholesterol by 43.2% to 55.9% and increased FMD by 29.3% to 42.5% (p<0.05 for both compared with baselines). Both doses inhibited ROCK activity (p<0.05), and the extent of inhibition was greater with rosuvastatin 40 mg compared with 10 mg (p<0.05). Only rosuvastatin 40 mg significantly reduced hsCRP (p<0.05).There was no correlation between changes in ROCK activity and changes in low-density lipoprotein cholesterol (r=0.37, p>0.05 vs. r=0.41, p>0.05) among patients randomized to rosuvastatin 10 mg group or 40 mg group. There was a correlation between ROCK inhibition and change in FMD among patients with rosuvastatin 10 mg therapy (r=0.43, p<0.05), and 40 mg therapy (r=0.54, p<0.05). Correlation was found between changes in ROCK inhibition and changes in CRP in rosuvastatin 40 mg/day group (r=0.47, p<0.05).
These results demonstrate that high dose rosuvastatin exerts greater effects on LDL-C, ROCK activity, and CRP than low dose rosuvastatin. These findings provide clinical evidence that statins are effective in improving endothelium dysfunction by a cholesterol-independent mechanism in patients with atherosclerosis.
HMG-CoA还原酶抑制剂（他汀类药物）可抑制胆固醇生物合成，还能减少Rho激酶（ROCK）途径激活所需的类异戊二烯中间体的形成。ROCK途径在包括动脉硬化在内的心血管疾病中起关键作用。有研究表明，抑制ROCK可逆转动脉粥样硬化患者的血管功能障碍。然而，尚不清楚用于降低胆固醇水平的他汀类药物剂量是否能抑制动脉粥样硬化患者的ROCK活性。
在一项随机双盲研究中，我们对40例稳定型动脉粥样硬化患者给予瑞舒伐他汀10毫克/天或40毫克/天治疗，为期28天。我们评估了他汀类药物治疗前后血脂水平、C反应蛋白（CRP）、ROCK活性以及肱动脉血流介导的血管舒张功能（FMD）的变化。
瑞舒伐他汀10毫克和40毫克治疗组的低密度脂蛋白胆固醇（LDL胆固醇）显著降低43.2%至55.9%，FMD增加29.3%至42.5%（与基线相比，两者p均<0.05）。两种剂量均抑制ROCK活性（p<0.05），且40毫克瑞舒伐他汀的抑制程度大于10毫克瑞舒伐他汀（p<0.05）。只有40毫克瑞舒伐他汀显著降低了高敏CRP（p<0.05）。在随机分为瑞舒伐他汀10毫克组或40毫克组的患者中，ROCK活性变化与低密度脂蛋白胆固醇变化之间无相关性（r=0.37，p>0.05；r=0.41，p>0.05）。在接受10毫克瑞舒伐他汀治疗的患者中，ROCK抑制与FMD变化之间存在相关性（r=0.43，p<0.05），在接受40毫克治疗的患者中也存在相关性（r=0.54，p<0.05）。在瑞舒伐他汀40毫克/天治疗组中，ROCK抑制变化与CRP变化之间存在相关性（r=0.47，p<0.05）。
这些结果表明，高剂量瑞舒伐他汀对LDL-C、ROCK活性和CRP的影响大于低剂量瑞舒伐他汀。这些发现提供了临床证据，表明他汀类药物可通过非胆固醇依赖机制有效改善动脉粥样硬化患者的内皮功能障碍。
