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.