title: Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice.
abstract: Leukocyte chemotaxis is deemed instrumental in initiation and progression of atherosclerosis. It is mediated by G-protein-coupled receptors (e.g., CCR2 and CCR5), the activity of which is controlled by G-protein-coupled receptor kinases (GRKs). In this study, we analyzed the effect of hematopoietic deficiency of a potent regulator kinase of chemotaxis (GRK2) on atherogenesis. LDL receptor-deficient (LDLr(-/-)) mice with heterozygous hematopoietic GRK2 deficiency, generated by bone marrow transplantation (n=15), displayed a dramatic attenuation of plaque development, with 79% reduction in necrotic core and increased macrophage content. Circulating monocytes decreased and granulocytes increased in GRK2(+/-) chimeras, which could be attributed to diminished granulocyte colony-forming units in bone marrow. Collectively, these data pointed to myeloid cells as major mediators of the impaired atherogenic response in GRK2(+/-) chimeras. LDLr(-/-) mice with macrophage/granulocyte-specific GRK2 deficiency (LysM-Cre GRK2(flox/flox); n=8) failed to mimic the aforementioned phenotype, acquitting these cells as major responsible subsets for GRK2 deficiency-associated atheroprotection. To conclude, even partial hematopoietic GRK2 deficiency prevents atherosclerotic lesion progression beyond the fatty streak stage, identifying hematopoietic GRK2 as a potential target for intervention in atherosclerosis.
authors.affiliation: Experimental Vascular Pathology Group, Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jeroen J T
authors.initials: JJ
authors.lastname: Otten
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Tom
authors.initials: T
authors.lastname: Seijkens
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Erwin
authors.initials: E
authors.lastname: Wijnands
authors.forename: Linda
authors.initials: L
authors.lastname: Beckers
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Westra
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Matthias
authors.initials: M
authors.lastname: Busch
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bermudez
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2