title: The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity.
abstract: Circulating levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease, and HDL and the HDL receptor scavenger receptor class B type I (SR-BI) initiate signaling in endothelium through src that promotes endothelial NO synthase activity and cell migration. Such signaling requires the C-terminal PDZ-interacting domain of SR-BI. Here we show that the PDZ domain-containing protein PDZK1 is expressed in endothelium and required for HDL activation of endothelial NO synthase and cell migration; in contrast, endothelial cell responses to other stimuli, including vascular endothelial growth factor, are PDZK1-independent. Coimmunoprecipitation experiments reveal that Src interacts with SR-BI, and this process is PDZK1-independent. PDZK1 also does not regulate SR-BI abundance or plasma membrane localization in endothelium or HDL binding or cholesterol efflux. Alternatively, PDZK1 is required for HDL/SR-BI to induce Src phosphorylation. Paralleling the in vitro findings, carotid artery reendothelialization following perivascular electric injury is absent in PDZK1-/- mice, and this phenotype persists in PDZK1-/- mice with genetic reconstitution of PDZK1 expression in liver, where PDZK1 modifies SR-BI abundance. Thus, PDZK1 is uniquely required for HDL/SR-BI signaling in endothelium, and through these mechanisms, it is critically involved in the maintenance of endothelial monolayer integrity.
authors.affiliation: Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, USA.
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.forename: Sonika
authors.initials: S
authors.lastname: Saddar
authors.forename: Divya
authors.initials: D
authors.lastname: Seetharam
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.forename: Christopher
authors.initials: C
authors.lastname: Longoria
authors.forename: David L
authors.initials: DL
authors.lastname: Silver
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002417:Cattle; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D050794:STAT1 Transcription Factor / Q000502:physiology; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism
chemical_list: D008075:Lipoproteins, HDL; D008565:Membrane Proteins; C509767:Pdzk1ip1 protein, mouse; D050794:STAT1 Transcription Factor; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse