title: Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.
abstract: OBJECTIVE
  Kalirin is a multifunctional protein that contains 2 guanine nucleotide exchange factor domains for the GTPases Rac1 and RhoA. Variants of KALRN have been associated with atherosclerosis in humans, but Kalirin's activity has been characterized almost exclusively in the central nervous system. We therefore tested the hypothesis that Kalirin functions as a Rho-guanine nucleotide exchange factor in arterial smooth muscle cells (SMCs).
  
  
  RESULTS
  Kalirin-9 protein is expressed abundantly in aorta and bone marrow, as well as in cultured SMCs, endothelial cells, and macrophages. Moreover, arterial Kalirin was upregulated during early atherogenesis in apolipoprotein E-deficient mice. In cultured SMCs, signaling was affected similarly in 3 models of Kalirin loss-of-function: heterozygous Kalrn deletion, Kalirin RNAi, and treatment with the Kalirin Rho-guanine nucleotide exchange factor -1 inhibitor 1-(3-nitrophenyl)-1H-pyrrole-2,5-dione. With reduced Kalirin function, SMCs showed normal RhoA activation but diminished Rac1 activation, assessed as reduced Rac-GTP levels, p21-activated kinase autophosphorylation, and SMC migration. Kalrn(-/+) SMCs proliferated 30% less rapidly than wild-type SMCs. Neointimal hyperplasia engendered by carotid endothelial denudation was ≈60% less in Kalrn(-/+) and SMC-specific Kalrn(-/+) mice than in control mice.
  
  
  CONCLUSIONS
  Kalirin functions as a guanine nucleotide exchange factor for Rac1 in SMCs, and promotes SMC migration and proliferation both in vitro and in vivo.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jiao-Hui
authors.initials: JH
authors.lastname: Wu
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Fanaroff
authors.forename: Krishn C
authors.initials: KC
authors.lastname: Sharma
authors.forename: Liisa S
authors.initials: LS
authors.lastname: Smith
authors.forename: Leigh
authors.initials: L
authors.lastname: Brian
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Freedman
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058426:Neointima; D009479:Neuropeptides / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; C484602:Rac1 protein, mouse; D054462:p21-Activated Kinases; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein