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Assembly and Characterization of Polyelectrolyte Complex Micelles

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Published on: March 2, 2020

Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis.

Sanguk Yun¹, Rui Hu¹, Melanie E Schwaemmle¹

¹Department of Internal Medicine, Yale Cardiovascular Research Center, and.

The Journal of Clinical Investigation

|August 14, 2019

Summary

Fibronectin activates endothelial cells via phosphodiesterase 4D5 (PDE4D5) in vascular remodeling and atherosclerosis. Inhibiting this interaction reduced inflammation and plaque size in mice, revealing a new therapeutic target.

Keywords:

Atherosclerosis Cell Biology Fibronectin Phosphoprotein phosphatases Vascular Biology

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Quantification of Atherosclerosis in Mice

Quantification of Atherosclerosis in Mice

Published on: June 12, 2019

Area of Science:

Vascular Biology
Cell Signaling
Atherosclerosis Research

Background:

Fibronectin in vascular walls drives endothelial inflammation and atherosclerosis.
This process involves integrin α5 binding to phosphodiesterase 4D5 (PDE4D5), leading to its activation and hydrolysis of anti-inflammatory cAMP.
Activated PDE4D5 promotes inflammatory signaling, contributing to vascular remodeling and disease progression.

Purpose of the Study:

To investigate the in vivo role of PDE4D5 in fibronectin-mediated endothelial activation and atherosclerosis.
To elucidate the mechanism of PDE4D5 activation by integrin signaling.
To identify novel therapeutic strategies targeting the fibronectin-integrin-PDE4D5 axis.

Main Methods:

In vivo studies using genetically modified mice with a mutated integrin binding site in PDE4D5.
Assessment of endothelial inflammatory activation in athero-prone arterial regions.
Analysis of atherosclerotic plaque size and stability markers in a hyperlipidemia model.
Proteomic analysis to identify PDE4D5-interacting proteins and regulatory complexes.

Main Results:

Mutation of the integrin binding site in PDE4D5 significantly reduced endothelial inflammatory activation.
In a hyperlipidemia model, this mutation decreased atherosclerotic plaque size and increased plaque stability markers.
Proteomics identified the PP2A regulatory subunit B55α as a key component in recruiting PP2A to PDE4D5, facilitating its dephosphorylation and activation.
The PDE4D5-PP2A-B55α complex also dephosphorylated and activated the transcription factor Yap.

Conclusions:

PDE4D5 acts as a crucial mediator of matrix-specific endothelial cell (EC) phenotype regulation through an unconventional adapter role.
The fibronectin-integrin-PDE4D5-PP2A-B55α pathway represents a novel mechanism controlling EC inflammatory responses and atherosclerotic development.
Targeting this pathway holds potential for therapeutic interventions in vascular diseases like atherosclerosis.