title: HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation.
abstract: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert modulatory effects on a number of cell signaling cascades by preventing the synthesis of various isoprenoids derived from the mevalonate pathway. In the present study, we describe a novel pleiotropic effect of HMG-CoA reductase inhibitors, also commonly known as statins, on vascular endothelial growth factor (VEGF)-induced type IV collagen accumulation. VEGF is an angiogenic polypeptide that is also known to play a central role in endothelial cell permeability and differentiation. Recently, VEGF has also been implicated in promoting extracellular matrix (ECM) accumulation, although the precise signaling mechanism that mediates VEGF-induced ECM expansion remains poorly characterized. Elucidation of the mechanisms through which VEGF exerts its effect on ECM is clearly a prerequisite for both understanding the complex biology of this molecule as well as targeting VEGF in several pathological processes. To this end, this study explored the underlying molecular mechanisms mediating VEGF-induced ECM expansion in mesangial cells. Our findings show that VEGF stimulation elicits a robust increase in ECM accumulation that involves RhoA activation, an intact actin cytoskeleton, and beta(1)- integrin activation. Our data also indicate that simvastatin, via mevalonate depletion, reverses VEGF-induced ECM accumulation by preventing RhoA activation.
authors.affiliation: Feinberg School of Medicine, Northwestern Univ., 303 E. Chicago Ave., Searle Bldg. 10-440, Chicago, IL 60611, USA.
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
authors.forename: Lixia
authors.initials: L
authors.lastname: Zeng
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Sheldon
authors.initials: S
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jones
authors.forename: Teng-Leong
authors.initials: TL
authors.lastname: Chew
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.forename: Farhad R
authors.initials: FR
authors.lastname: Danesh
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000493:pharmacokinetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D014316:Tritium; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D024141:Collagen Type IV; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019012:Integrin beta1; D042461:Vascular Endothelial Growth Factor A; D014316:Tritium; D014443:Tyrosine; D011392:Proline; D019821:Simvastatin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid