The Mevalonate Cascade as a Target to Suppress Extracellular Matrix Synthesis by Human Airway Smooth Muscle
| Autor: | Gordon Dueck, Helmut Unruh, Saeid Ghavami, Grant M. Hatch, Andrew J. Halayko, Andrea Kroeker, Dedmer Schaafsma, Karol D. McNeill, Mark M. Mutawe, Kristin Hauff, Fred Y. Xu |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Pulmonary and Respiratory Medicine
Simvastatin medicine.medical_specialty Clinical Biochemistry Mevalonic Acid Reductase Models Biological Collagen Type I Transforming Growth Factor beta1 Extracellular matrix chemistry.chemical_compound Leucine Internal medicine medicine Farnesyltranstransferase Humans Myocyte Secretion Molecular Biology Alkyl and Aryl Transferases biology Reverse Transcriptase Polymerase Chain Reaction Cholesterol nutritional and metabolic diseases Cell Biology Extracellular Matrix Cell biology Trachea Fibronectin Endocrinology Gene Expression Regulation chemistry biology.protein lipids (amino acids peptides and proteins) Collagen Protein Processing Post-Translational Transforming growth factor medicine.drug |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 44:394-403 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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