Recent　studies　have　shown　that　statins　ameliorate　hypoxia-induced　pulmonary　hypertension　in　animal　models.　Yet,　the　underlying　molecular　mechanisms　have　not　been　completely　understood.　Here,　we　investigated　the　hypothesis　that　statins　regulate　vascular　remodeling　by　modulation　of　matrix　metalloproteinases　(MMP)　secretion　in　primary　cultured　pulmonary　artery　smooth　muscle　cells　(PASMCs).　Angiotensin　II　induced　a　concentration-dependent　MMP2　secretion.　A　2.75　fold　increase　was　achieved　by　100　nM　angiotensin　II　stimulation　for　24　h　in　primary　cultured　PASMCs　(P　＜　0.01　versus　control),　which　was　reversed　by　silencing　Ras　homolog　gene　family　member　A　(RhoA)　or　inhibition　of　its　downstream　Rho-associated　kinase　(ROCK).　There　was　no　effect　of　angiotensin　II　on　the　expression　of　tissue　inhibitors　of　matrix　metalloproteinases　(TIMPs).　Pre-exposure　of　cells　to　simvastatin　concentration-dependently　blocked　angiotensin　II-stimulated　MMP2　release.　MMP2　release　was　reduced　to1.34　fold　increase　in　the　presence　of　10　mu　M　simvastatin　(P　＜　0.01　versus　angiotensin　II-stimulated　cells).　We　further　revealed　that　simvastatin　suppression　of　RhoA　activation　mediated　its　inhibitory　effect　on　angiotensin　II-triggered　MMP2　release.　Similarly,　simvastatin　suppressed　endothelin-1-induced　MMP2　release　through　RhoA/ROCK　pathway.　These　results　indicated　a　novel　statins-regulation　of　RhoA/ROCK　signaling　against　pulmonary　vascular　remodeling,　and　suggest　that　statins　could　prove　useful　in　targeting　this　pathway　in　pulmonary　hypertension　and　other　disease　conditions.　(C)　2008　Elsevier　B.V.　All　rights　reserved.