title: Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice.
abstract: Pak1 plays an important role in various cellular processes, including cell motility, polarity, survival and proliferation. To date, its role in atherogenesis has not been explored. Here we report the effect of Pak1 on atherogenesis using atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice as a model. Disruption of Pak1 in ApoE(-/-) mice results in reduced plaque burden, significantly attenuates circulating IL-6 and MCP-1 levels, limits the expression of adhesion molecules and diminishes the macrophage content in the aortic root of ApoE(-/-) mice. We also observed reduced oxidized LDL uptake and increased cholesterol efflux by macrophages and smooth muscle cells of ApoE(-/-):Pak1(-/-) mice as compared with ApoE(-/-) mice. In addition, we detect increased Pak1 phosphorylation in human atherosclerotic arteries, suggesting its role in human atherogenesis. Altogether, these results identify Pak1 as an important factor in the initiation and progression of atherogenesis.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, Tennessee 38163, USA.
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, Tennessee 38163, USA.
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Kotla
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, Tennessee 38163, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Dyukova
authors.affiliation: Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana 71103, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Traylor
authors.affiliation: Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana 71103, USA.
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Tony N
authors.initials: TN
authors.lastname: Marion
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, Tennessee 38163, USA.
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases