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All rights reserved. http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_6 http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/version 20131211 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_4 http://purl.org/dc/elements/1.1/identifier AHA Abstracts 621 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_4 http://purl.org/dc/elements/1.1/title AHA Abstracts 621 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_4 http://purl.org/dc/elements/1.1/type Other http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_5 http://www.w3.org/ns/prov#value 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have shown beneficial effects in the treatment of cardiovascular diseases as lipid lowering drugs. Recent work points to cholesterol-independent actions such as inhibition of isoprenylation and activation of G proteins. Angiotensin II (AngII) participates in the development of fibrosis during vascular damage. Connective tissue growth factor (CTGF) has been described as a novel fibrotic mediator. Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate AngII responses, investigating in vascular smooth muscle cells the effect on CTGF expression. Results: In growth-arrested VSMC, AngII, via AT1 receptor, induced CTGF mRNA expression (Northern) and protein production (5-fold vs control; 10-7 mol/L AngII at 24 h; Western). A CTGF antisense oligonucleotide decreased AngII-induced fibronectin synthesis, suggesting that CTGF could be a mediator of fibrogenic effects of AngII. Pretreatment of VSMC with simvastatin (10-7 mol/L to 10-10mol/L) time and dose-dependently inhibited AngII-induced CTGF production (maximal 10-7mol/L: 80% inhibition vs AngII; Western). The inhibition of CTGF expression was prevented when cells were incubated with mevalonate, geranylgeranylpyrophosphate and, in a lesser extend, with farnesylpyrophospate. Different receptors coupled to G proteins, including AT1, activate p21ras and Rho kinase. Overexpression of dominant negative mutant of RhoA suppressed CTFG induction by AngII. The inhibitor of Rho kinase Y-27632, dose-dependently decreased AngII-induced CTGF production, implicating RhoA as a signaling module downstream of AngII and showing that the Rho-kinase pathway may be a novel target to inhibit AngII signaling. Conclusions: Our data suggest that HMG-CoA reductase inhibitors, via Rho proteins, regulate AngII-induced CTGF, a protein related to the development of fibrosis, suggesting that some of the beneficial effects of these drugs could be due to modulation of AngII-mediated vascular damage, explaining cholesterol independent protective effects. http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_5 http://www.w3.org/ns/prov#wasQuotedFrom http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_4 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_6 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_4 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#_5 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA#pubinfo http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA http://purl.org/dc/terms/created 2014-07-03T14:31:27.384+02:00 http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAHTTaBVO2O8KTus9Wi4LOX4FfpL4o1Zp3dvzIL133BIA http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234