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: Weifei Zhu, Sonika Saddar, Divya Seetharam, Ken L Chambliss, Christopher Longoria, David L Silver, Ivan S Yuhanna, Philip W Shaul, Chieko Mineo
• Journal: Circulation research (Circ Res) Vol. 102 Issue 4 Pg. 480-7 (Feb 29 2008) ISSN: 1524-4571 [Electronic] United States
• PMID: 18174467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoproteins, HDL
• Membrane Proteins
• Pdzk1ip1 protein, mouse
• STAT1 Transcription Factor
• Scarb1 protein, mouse
• Scavenger Receptors, Class B
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse

Topics

• Animals
• Aorta (cytology)
• Cattle
• Cell Movement (physiology)
• Cells, Cultured
• Endothelial Cells (cytology, metabolism)
• Enzyme Activation (physiology)
• Lipoproteins, HDL (metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Mutant Strains
• Nitric Oxide Synthase Type II (metabolism)
• Nitric Oxide Synthase Type III
• STAT1 Transcription Factor (physiology)
• Scavenger Receptors, Class B (metabolism)
• Tunica Intima (cytology, metabolism)