Inhibition of Vascular Smooth Muscle Cell Perk/ATF4 Er Stress Signaling Protects Against Abdominal Aortic Aneurysms

Authors

Brennan Callow
Xiaobing He
Nicholas Juriga
Kevin D Mangum
Amrita Joshi
Xianying Xing
Andrea Obi
Abhijnan Chattopadhyay
Dianna M Milewicz
Mary X O'Riordan
Johann Gudjonsson
Katherine Gallagher
Frank M Davis

Language

English

Publication Date

1-23-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.183959

PMID

39846252

PMCID

PMC11790032

PubMedCentral® Posted Date

1-23-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response. Mechanistically, we reported that aberrant TNF-α activity within the aortic wall induces VSMC ATF4 activation through the PERK endoplasmic reticulum stress response, resulting in progressive apoptosis. In vivo targeted inhibition of the PERK pathway, with VSMC-specific genetic depletion (Eif2ak3fl/fl Myh11-CreERT2) or pharmacological inhibition in the elastase and angiotensin II-induced AAA model preserved VSMC function, decreased elastin fragmentation, attenuated VSMC apoptosis, and markedly reduced AAA expansion. Together, our findings suggest that cell-specific pharmacologic therapy targeting the PERK/eIF2α/ATF4 pathway in VSMCs may be an effective intervention to prevent AAA expansion.

Keywords

Activating Transcription Factor 4, eIF-2 Kinase, Muscle, Smooth, Vascular, Endoplasmic Reticulum Stress, Aortic Aneurysm, Abdominal, Animals, Humans, Mice, Signal Transduction, Apoptosis, Male, Myocytes, Smooth Muscle, Disease Models, Animal, Eukaryotic Initiation Factor-2, Angiotensin II, Mice, Inbred C57BL, Vascular biology, Cardiovascular disease, Cell stress, Surgery

Published Open-Access

yes

Recommended Citation

Callow, Brennan; He, Xiaobing; Juriga, Nicholas; et al., "Inhibition of Vascular Smooth Muscle Cell Perk/ATF4 Er Stress Signaling Protects Against Abdominal Aortic Aneurysms" (2025). Faculty, Staff and Student Publications. 6271.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6271