title: Inhibition of Rho and Rac geranylgeranylation by atorvastatin is critical for preservation of endothelial junction integrity.
abstract: BACKGROUND
  Small GTPases (guanosine triphosphate, GTP) are involved in many critical cellular processes, including inflammation, proliferation, and migration. GTP loading and isoprenylation are two important post-translational modifications of small GTPases, and are critical for their normal function. In this study, we investigated the role of post-translational modifications of small GTPases in regulating endothelial cell inflammatory responses and junctional integrity.
  
  
  RESULTS
  Confluent human umbilical vein endothelial cell (HUVECs ) treated with atorvastatin demonstrated significantly decreased lipopolysaccharide (LPS)-mediated IL-6 and IL-8 generation. The inhibitory effect of atorvastatin (Atorva) was attenuated by co-treatment with 100 µM mevalonate (MVA) or 10 µM geranylgeranyl pyrophosphate (GGPP), but not by 10 µM farnesyl pyrophosphate (FPP). Atorvastatin treatment of HUVECs produced a time-dependent increase in GTP loading of all Rho GTPases, and induced the translocation of small Rho GTPases from the cellular membrane to the cytosol, which was reversed by 100 µM MVA and 10 µM GGPP, but not by 10 µM FPP. Atorvastatin significantly attenuated thrombin-induced HUVECs permeability, increased VE-cadherin targeting to cell junctions, and preserved junction integrity. These effects were partially reversed by GGPP but not by FPP, indicating that geranylgeranylation of small GTPases plays a major role in regulating endothelial junction integrity. Silencing of small GTPases showed that Rho and Rac, but not Cdc42, play central role in HUVECs junction integrity.
  
  
  CONCLUSIONS
  In conclusion, our studies show that post-translational modification of small GTPases plays a vital role in regulating endothelial inflammatory response and endothelial junction integrity. Atorvastatin increased GTP loading and inhibited isoprenylation of small GTPases, accompanied by reduced inflammatory response and preserved cellular junction integrity.
authors.affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China. xhb63@yahoo.cn
authors.forename: Hongbing
authors.initials: H
authors.lastname: Xiao
authors.forename: Xiong
authors.initials: X
authors.lastname: Qin
authors.forename: Ding
authors.initials: D
authors.lastname: Ping
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zuo
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000069059:Atorvastatin; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007365:Intercellular Junctions / Q000187:drug effects* / Q000201:enzymology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D054876:Prenylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000069059:Atorvastatin; D015820:Cadherins; D006160:Guanosine Triphosphate; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008798:Mevalonic Acid; D011106:Polyisoprenyl Phosphates; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles; D012717:Sesquiterpenes; D013917:Thrombin; D020764:cdc42 GTP-Binding Protein; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C508600:IL6 protein, human; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate
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