Abstract
Scavenger receptor class B, type I (SR-BI) and its adaptor protein PDZK1 mediate responses to HDL cholesterol in endothelium. Whether the receptor-adaptor protein tandem serves functions in other vascular cell types is unknown. The current work determined the roles of SR-BI and PDZK1 in vascular smooth muscle (VSM). To evaluate possible VSM functions of SR-BI and PDZK1 in vivo, neointima formation was assessed 21 days post-ligation in the carotid arteries of wild-type, SR-BI-/- or PDZK1-/- mice. Whereas neointima development was negligible in wild-type and SR-BI-/-, there was marked neointima formation in PDZK1-/- mice. PDZK1 expression was demonstrated in primary mouse VSM cells, and compared to wild-type cells, PDZK1-/- VSM displayed exaggerated proliferation and migration in response to platelet derived growth factor (PDGF). Tandem affinity purification-mass spectrometry revealed that PDZK1 interacts with breakpoint cluster region kinase (Bcr), which contains a C-terminal PDZ binding sequence and is known to enhance responses to PDGF in VSM. PDZK1 interaction with Bcr in VSM was demonstrated by pull-down and by coimmunoprecipitation, and the augmented proliferative response to PDGF in PDZK1-/- VSM was abrogated by Bcr depletion. Furthermore, compared with wild-type Bcr overexpression, the introduction of a Bcr mutant incapable of PDZK1 binding into VSM cells yielded an exaggerated proliferative response to PDGF. Thus, PDZK1 has novel SR-BI-independent function in VSM that affords protection from neointima formation, and this involves PDZK1 suppression of VSM cell proliferation via an inhibitory interaction with Bcr.
Highlights
In endothelial cells, high density lipoprotein (HDL) cholesterol binding to scavenger receptor class B, type I (SR-BI) activates PI3 kinase and Akt kinase to stimulate endothelial NO synthase and endothelial cell migration[1,2]
To determine how SR-BI impacts neointima formation, neointima development following carotid artery ligation was evaluated in SR-BI+/+ and SR-BI-/- mice
Via signaling prompted by HDL-induced cholesterol movement, SR-BI and PDZK1 activate kinases and thereby stimulate endothelial NO synthase (eNOS) and endothelial cell migration[9,33,34,35]
Summary
High density lipoprotein (HDL) cholesterol binding to scavenger receptor class B, type I (SR-BI) activates PI3 kinase and Akt kinase to stimulate endothelial NO synthase (eNOS) and endothelial cell migration[1,2]. Dysregulation of VSM cell behavior plays a major role in neointima development, which participates in the pathogenesis of nonthrombotic vascular occlusion, restenosis, atherosclerosis and vein-graft failure[5] These processes entail exaggerated VSM proliferation and migration prompted by inflammatory cytokines and growth factors such as tumor necrosis factor-α and platelet-derived growth factor (PDGF)[5,6,7,8]. The absence of SR-BI had no effect, PDZK1-/- mice uniquely demonstrated exaggerated neointima development This led to the discoveries that PDZK1 negatively regulates VSM cell growth and migration, and that this occurs via an inhibitory interaction of PDZK1 with breakpoint cluster region kinase (Bcr). PDZK1 warrants consideration as a modifier of neointima formation and restenosis
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