Rho‐dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)

摘要: It was supposed that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase (statins) might inhibit the expression fibrosis-related factor CTGF (connective tissue growth factor) by interfering with isoprenylation Rho proteins. The human renal fibroblast cell line TK173 used as an in vitro model system to study statin-mediated modulation structure actin cytoskeleton and mRNA. Incubation cells simvastatin or lovastatin time-dependently reversibly changed morphology maximal effects observed after about 18 h. Within same time period, statins reduced basal interfered induction lysophosphatidic acid (LPA) transforming beta. Simvastatin proved be much more potent than pravastatin (IC(50) 1 - 3 microM compared 500 microM). inhibition prevented when were incubated mevalonate geranylgeranylpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP). Specific geranylgeranyltransferase-I GTI-286 inhibited LPA-mediated whereas inhibitor farnesyltransferases FTI-276 ineffective. binding small GTPase RhoA cellular membranes. effect GGPP, FPP. These data are agreement hypothesis interference mRNA is primarily due RhoA, previous studies, which have shown essential mediator induction. direct synthesis CTGF, a protein functionally related development fibrosis, may thus novel mechanism underlying beneficial diseases.