Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts.
Simvastatin is best known for its antilipidemic action and use in cardiovascular disease due to its inhibition of 3-hydroxy-3-methylglutaryl CoenzymeA (HMG CoA) reductase, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. Connective tissue growth factor (CTGF) and persistent myofibroblast formation are major determinants of the aggressive fibrotic disease, idiopathic pulmonary fibrosis (IPF). In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on CTGF gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited (P < 0.05) CTGF gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of CTGF. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.
Watts
Keira L
KL
Lung Research, Institute of Science and Technology in Medicine, University Hospital of North Stafforshire/Keel University, School of Postgraduate Medicine, Thornburrow Drive, Hartshill, Stoke on Trent ST4 7NQ, UK. keira_watts@yahoo.co.uk
Sampson
Edith M
EM
Schultz
Gregory S
GS
Spiteri
Monica A
MA
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000199:Actins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001905:Botulinum Toxins / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005782:Gels; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors
D000199:Actins; D015415:Biomarkers; C526317:CCN2 protein, human; D005782:Gels; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen; D019821:Simvastatin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins