The Mevalonate Cascade as a Target to Suppress Extracellular Matrix Synthesis by Human Airway Smooth Muscle

Abstract

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.

Protein Prenylation Contributes to the Effects of LPS on EFS–Induced Responses in Human Isolated Bronchi

“…These findings suggest that statins, other than being effective in preventing prenylation-mediated AHR induced by LPS, may also play a pivotal role in the regulation of airway smooth muscle tone by triggering nitric oxide synthesis (57). Our results are in agreement with recent clinical findings that demonstrated a protective role of statins in patients suffering with asthma (58)(59)(60).…”

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration

“…Recent studies revealed that statins reduce RhoA activation by suppressing the mevalonate cascade and this inhibitory effect is related to geranylgeranylpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP), which lie downstream of mevalonate. Schaafsma et al showed that simvastatin suppresses expression of extracellular matrix components such as collagen I and fibronectin, which are induced by TGF-b1 in ASM cells [26]. They also reported that PDGF induced RhoA activation and ASM cell proliferation [27].…”

Innovations in asthma therapy: is there a role for inhaled statins?

“…Metabolites of the MA pathway, particularly the isoprenoids, have been associated with processes linked to asthma and respiratory ailments, including allergic eosinophilic inflammation [31,36,69], Rho GTPase signaling in airway smooth muscle cells and airway hyperreactivity (AHR) [48,70,71], adaptive immunity and type 2 inflammation [72,73], airway smooth muscle cell proliferation [43], and mucus production [74] (Figure 2). Since these pathogenic mechanisms occur in asthma, perturbation of the MA pathway likely affects disease pathogenesis [29,70].…”