Department of Physiology, Section of Respiratory Disease, University of Manitoba, Winnipeg, Manitoba, Canada.
Am J Respir Cell Mol Biol. 2011 Mar;44(3):394-403. doi: 10.1165/rcmb.2010-0052OC. Epub 2010 May 12.
Smooth muscle cells promote fibroproliferative airway remodeling in asthma, and transforming growth factor β1 (TGFβ1) is a key inductive signal. Statins are widely used to treat hyperlipidemia. Growing evidence indicates they also exert a positive impact on lung health, but the underlying mechanisms are unclear. We assessed the effects of 3-hydroxy-3-methlyglutaryl-coenzyme A (HMG-CoA) reductase inhibition with simvastatin on the fibrotic function of primary cultured human airway smooth muscle cells. Simvastatin blocked de novo cholesterol synthesis, but total myocyte cholesterol content was unaffected. Simvastatin also abrogated TGFβ1-induced collagen I and fibronectin expression, and prevented collagen I secretion. The depletion of mevalonate cascade intermediates downstream from HMG-CoA underpinned the effects of simvastatin, because co-incubation with mevalonate, geranylgeranylpyrophosphate, or farnesylpyrophosphate prevented the inhibition of matrix protein expression. We also showed that human airway myocytes express both geranylgeranyl transferase 1 (GGT1) and farnesyltransferase (FT), and the inhibition of GGT1 (GGTI inhibitor-286, 10 μM), but not FT (FTI inhibitor-277, 10 μM), mirrored the suppressive effects of simvastatin on collagen I and fibronectin expression and collagen I secretion. Moreover, simvastatin and GGTI-286 both prevented TGFβ1-induced membrane association of RhoA, a downstream target of GGT1. Our findings suggest that simvastatin and GGTI-286 inhibit synthesis and secretion of extracellular matrix proteins by human airway smooth muscle cells by suppressing GGT1-mediated posttranslational modification of signaling molecules such as RhoA. These findings reveal mechanisms related to evidence for the positive impact of statins on pulmonary health.
平滑肌细胞促进哮喘中的纤维增生性气道重塑，而转化生长因子β1（TGFβ1）是关键的诱导信号。他汀类药物被广泛用于治疗高脂血症。越来越多的证据表明，它们对肺部健康也有积极影响，但潜在机制尚不清楚。我们评估了用辛伐他汀抑制 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶对原代培养的人气道平滑肌细胞纤维化功能的影响。辛伐他汀阻断了新的胆固醇合成，但肌细胞总胆固醇含量不受影响。辛伐他汀还阻断了 TGFβ1 诱导的胶原 I 和纤维连接蛋白表达，并防止胶原 I 分泌。HMG-CoA 下游的甲羟戊酸级联中间产物的耗竭是辛伐他汀作用的基础，因为与甲羟戊酸、香叶基香叶基焦磷酸或法呢基焦磷酸共孵育可防止基质蛋白表达的抑制。我们还表明，人气道肌细胞表达法尼基转移酶 1（GGT1）和 farnesyltransferase（FT），并且抑制 GGT1（GGTI 抑制剂-286，10 μM），而不是 FT（FTI 抑制剂-277，10 μM），模拟了辛伐他汀对胶原 I 和纤维连接蛋白表达和胶原 I 分泌的抑制作用。此外，辛伐他汀和 GGTI-286 均可防止 TGFβ1 诱导 RhoA 的膜结合，RhoA 是 GGT1 的下游靶标。我们的研究结果表明，辛伐他汀和 GGTI-286 通过抑制 GGT1 介导的 RhoA 等信号分子的翻译后修饰，抑制人气道平滑肌细胞细胞外基质蛋白的合成和分泌。这些发现揭示了与他汀类药物对肺部健康的积极影响相关的机制。
