The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity

Weifei Zhu, Sonika Saddar, Divya Seetharam, Ken L. Chambliss, Christopher Longoria, David L. Silver, Ivan S. Yuhanna, Philip W. Shaul, Chieko Mineo

Research output: Contribution to journalArticle

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)480-487
Number of pages8
JournalCirculation research
Volume102
Issue number4
DOIs
StatePublished - Feb 1 2008

Keywords

  • Endothelium
  • High-density lipoprotein
  • PDZK1
  • SR-BI

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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