3-Hydroxymethyl coenzyme A reductase inhibition attenuates spontaneous smooth muscle tone via RhoA/ROCK pathway regulated by RhoA prenylation
3-Hydroxymethyl coenzyme A reductase inhibition attenuates spontaneous smooth muscle tone via RhoA/ROCK pathway regulated by RhoA prenylation
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DOI：
10.1152/ajpgi.00034.2010
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发表时间：
2010-06-01
影响因子：
4.5
通讯作者：
Rattan, Satish
中科院分区：
文献类型：
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作者：
Rattan, Satish
Rattan S. 3-羟甲基辅酶 A 还原酶抑制通过 RhoA 异戊二烯化调节的 RhoA/ROCK 途径减弱自发平滑肌张力。 Am J Physiol Gastrointest Liver Physiol 298：G962-G969，2010。首次发表于 2010 年 4 月 8 日； doi:10.1152/ajpgi.00034.2010.-RhoA 异戊二烯化可能在基底肛门内括约肌 (IAS) 平滑肌张力中 RhoA 易位中发挥重要作用。他汀类药物通过 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶抑制 (HMGCRI) 抑制下游 RhoA 翻译后异戊二烯化。尚未研究他汀类药物与 RhoA 异戊二烯化在自发强直平滑肌病理生理学中的作用。在本研究中，我们确定了经典 HMGCRI 辛伐他汀对基础 IAS 音调和 RhoA 异戊二烯化以及平滑肌细胞质与膜部分中 RhoA/Rho 激酶 (ROCK) 水平的影响。辛伐他汀引起 IAS 音调的浓度依赖性降低（通过直接作用于平滑肌细胞）。辛伐他汀对 IAS 音调的降低与基础状态下 IAS 膜部分中 RhoA 以及 RhoA/ROCK 异戊二烯化的降低有关。 HMGCRI 的抑制作用可被香叶基香叶基转移酶底物香叶基香叶基焦磷酸完全逆转。 HMGCRI 辛伐他汀对 IAS 平滑肌的松弛是通过下游 RhoA 异戊二烯化和 ROCK 活性水平的降低介导的。研究支持这样的概念：RhoA 异戊二烯化导致 RhoA/ROCK 易位，随后激活，对于 IAS 的基础音非常重要。数据表明，HMG-CoA 还原酶的作用可能超越胆固醇生物合成，例如调节平滑肌张力。这些研究对肛门直肠运动障碍的病理生理机制和新治疗方法具有重要意义。
Rattan S. 3-Hydroxymethyl coenzyme A reductase inhibition attenuates spontaneous smooth muscle tone via RhoA/ROCK pathway regulated by RhoA prenylation. Am J Physiol Gastrointest Liver Physiol 298: G962-G969, 2010. First published April 8, 2010; doi:10.1152/ajpgi.00034.2010.-RhoA prenylation may play an important step in the translocation of RhoA in the basal internal anal sphincter (IAS) smooth muscle tone. Statins inhibit downstream posttranslational RhoA prenylation by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition (HMGCRI). The role of statins in relation to RhoA prenylation in the pathophysiology of the spontaneously tonic smooth muscle has not been investigated. In the present studies, we determined the effect of classical HMGCRI simvastatin on the basal IAS tone and RhoA prenylation and in the levels of RhoA/Rho kinase (ROCK) in the cytosolic vs. membrane fractions of the smooth muscle. Simvastatin produced concentration-dependent decrease in the IAS tone (via direct actions at the smooth muscle cells). The decrease in the IAS tone by simvastatin was associated with the decrease in the prenylation of RhoA, as well as RhoA/ROCK in the membrane fractions of the IAS, in the basal state. The inhibitory effects of the HMGCRI were completely reversible by geranylgeranyltransferase substrate geranylgeranyl pyrophosphate. Relaxation of the IAS smooth muscle via HMGCRI simvastatin is mediated via the downstream decrease in the levels of RhoA prenylation and ROCK activity. Studies support the concept that RhoA prenylation leading to RhoA/ROCK translocation followed by activation is important for the basal tone in the IAS. Data suggest that the role of HMG-CoA reductase may go beyond cholesterol biosynthesis, such as the regulation of the smooth muscle tone. The studies have important implications in the pathophysiological mechanisms and in the novel therapeutic approaches for anorectal motility disorders.