EVA1A (Eva-1 Homolog A) Promotes Endothelial Apoptosis and Inflammatory Activation Under Disturbed Flow Via Regulation of Autophagy

Lindsay Canham, Sam Sendac, Mannekomba R. Diagbouga, Elena Wolodimeroff, Daniela Pirri, Blanca Tardajos Ayllon, Shuang Feng, Celine Souilhol, Timothy J.A. Chico, Paul C. Evans, Jovana Serbanovic-Canic

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)

Abstract

Background:
Hemodynamic wall shear stress (WSS) exerted on the endothelium by flowing blood determines the spatial distribution of atherosclerotic lesions. Disturbed flow (DF) with a low WSS magnitude and reversing direction promotes atherosclerosis by regulating endothelial cell (EC) viability and function, whereas un-DF which is unidirectional and of high WSS magnitude is atheroprotective. Here, we study the role of EVA1A (eva-1 homolog A), a lysosome and endoplasmic reticulum-associated protein linked to autophagy and apoptosis, in WSS-regulated EC dysfunction.

Methods:
The effect of WSS on EVA1A expression was studied using porcine and mouse aortas and cultured human ECs exposed to flow. EVA1A was silenced in vitro in human ECs and in vivo in zebrafish using siRNA and morpholinos, respectively.

Results:
EVA1A was induced by proatherogenic DF at both mRNA and protein levels. EVA1A silencing resulted in decreased EC apoptosis, permeability, and expression of inflammatory markers under DF. Assessment of autophagic flux using the autolysosome inhibitor, bafilomycin coupled to the autophagy markers LC3-II and p62, revealed that EVA1A knockdown promotes autophagy when ECs are exposed to DF, but not un-DF . Blocking autophagic flux led to increased EC apoptosis in EVA1A-knockdown cells exposed to DF, suggesting that autophagy mediates the effects of DF on EC dysfunction. Mechanistically, EVA1A expression was regulated by flow direction via transcription factor TWIST1. In vivo, knockdown of EVA1A orthologue in zebrafish resulted in reduced EC apoptosis, confirming the proapoptotic role of EVA1A in the endothelium.

Conclusions:
We identified EVA1A as a novel flow-sensitive gene that mediates the effects of proatherogenic DF on EC dysfunction by regulating autophagy.
Original languageEnglish
Pages (from-to)547-561
Number of pages15
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume43
Issue number4
Early online date16 Feb 2023
DOIs
Publication statusPublished - 22 Apr 2023

Bibliographical note

Funding Information:
This study was supported by the British Heart Foundation Programme Grants (RG/13/1/30042 and RG/19/10/34506; P.C. Evans) and a British Heart Foundation Intermediate Fellowship (FS/18/2/33221; J. Serbanovic-Canic).

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

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