title: G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.
abstract: OBJECTIVE
  G protein-coupled receptor kinase-5 (GRK5) is a widely expressed Ser/Thr kinase that regulates several atherogenic receptors and may activate or inhibit nuclear factor-κB (NF-κB). This study sought to determine whether and by what mechanisms GRK5 affects atherosclerosis.
  
  
  RESULTS
  Grk5(-/-)/Apoe(-/-) mice developed 50% greater aortic atherosclerosis than Apoe(-/-) mice and demonstrated greater proliferation of macrophages and smooth muscle cells (SMCs) in atherosclerotic lesions. In Apoe(-/-) mice, carotid interposition grafts from Grk5(-/-) mice demonstrated greater upregulation of cell adhesion molecules than grafts from wild-type mice and, subsequently, more atherosclerosis. By comparing Grk5(-/-) with wild-type cells, we found that GRK5 desensitized 2 key atherogenic receptor tyrosine kinases: the platelet-derived growth factor receptor-β in SMCs, by augmenting ubiquitination/degradation; and the colony-stimulating factor-1 receptor (CSF-1R) in macrophages, by reducing CSF-1-induced tyrosyl phosphorylation. GRK5 activity in monocytes also reduced migration promoted by the 7-transmembrane receptor for monocyte chemoattractant protein-1 CC chemokine receptor-2. Whereas GRK5 diminished NF-κB-dependent gene expression in SMCs and endothelial cells, it had no effect on NF-κB activity in macrophages.
  
  
  CONCLUSIONS
  GRK5 attenuates atherosclerosis through multiple cell type-specific mechanisms, including reduction of SMC and endothelial cell NF-κB activity and desensitization of receptor-specific signaling through the monocyte CC chemokine receptor-2, macrophage CSF-1R, and the SMC platelet-derived growth factor receptor-β.
authors.affiliation: Box 3187, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jiao-Hui
authors.initials: JH
authors.lastname: Wu
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Fanaroff
authors.forename: Xinjiang
authors.initials: X
authors.lastname: Cai
authors.forename: Krishn C
authors.initials: KC
authors.lastname: Sharma
authors.forename: Leigh
authors.initials: L
authors.lastname: Brian
authors.forename: Sabrina T
authors.initials: ST
authors.lastname: Exum
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Shenoy
authors.forename: Karsten
authors.initials: K
authors.lastname: Peppel
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Freedman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016328:NF-kappa B; D054390:Receptors, CCR2; D047888:Receptors, Tumor Necrosis Factor, Type I; C493487:Tlr4 protein, mouse; C506236:Tnfrsf1a protein, mouse; D051197:Toll-Like Receptor 4; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse
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