Journal Article

Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis

Attanasio, John, Traylor, James G., Libreros, Stephania, Joshi, Nikhil, Deng, Hanqiang, Chakraborty, Raja, Orr, Anthony Wayne, Babar, Muhammad Usman, Fernandez-Tussy, Pablo, Fernandez-Hernando, Carlos, Schwartz, Martin A., Joshi, Divyesh, Meredith, Emily, Yang, Ziyu, Coon, Brian G.

2024

Overview

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD.

• Publisher: Nature Publishing Group,Nature Publishing Group UK
• Subject: Animals / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - metabolism / Cadherin Related Proteins / Cadherins - genetics / Cadherins - metabolism / Candidates / CRISPR / Disease Models, Animal / Endothelial Cells - metabolism / Experiments / Genes / Genomes / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Hypertension / Kinases / Kruppel-Like Factor 4 / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Plaque, Atherosclerotic - genetics / Plaque, Atherosclerotic - metabolism / Plaque, Atherosclerotic - pathology / Receptors, Notch - genetics / Receptors, Notch - metabolism / Shear stress / Signal Transduction / Statistical analysis / Variance analysis