Recent studies revealed an involvement of RhoA/
Rho-kinase in the contraction of bronchial smooth muscle (BSM), and this pathway has now been proposed as a new target for
asthma therapy. A posttranslational geranylgeranylation of RhoA is required for its activation. Thus selective inhibition of geranylgeranyltransferase may be a novel strategy for treatment of the BSM hyperresponsiveness in asthmatics. To test this hypothesis, we investigated the effect of a geranylgeranyltransferase inhibitor,
GGTI-2133, on
antigen-induced BSM hyperresponsiveness by using mice with experimental
asthma. Mice were sensitized and repeatedly challenged with
ovalbumin antigen. Animals also were treated with
GGTI-2133 (5 mg/kg ip) once a day before and during the
antigen inhalation period. Repeated
antigen inhalation caused a BSM hyperresponsiveness to
acetylcholine with the increased expressions of RhoA and the anti-farnesyl-positive 21-kDa
proteins, probably geranylgeranylated RhoA. The in vivo
GGTI-2133 treatments significantly inhibited BSM hyperresponsiveness induced by
antigen exposure. In another series of experiments, BSM tissues isolated from the repeatedly
antigen-challenged mice were cultured for 48 h in the absence or presence of
GGTI-2133. Under these conditions, the putative geranylgeranylated RhoA was decreased in a
GGTI-2133 concentration-dependent manner. The in vitro incubation with
GGTI-2133 also inhibited BSM hyperresponsiveness induced by
antigen exposure. These findings suggest that
GGTI-2133 inhibits
antigen-induced BSM hyperresponsiveness, probably by reducing downstream signal transduction of RhoA. Selective geranylgeranyltransferase inhibitors may be beneficial for the treatment of
airway hyperresponsiveness, one of the characteristic features of allergic
bronchial asthma.