ACTA2 Pathogenic Variants Activating Heat Shock Factor 1 and Increasing Cholesterol Biosynthesis in Smooth Muscle Cells Predispose to Early Onset Atherosclerosis

Authors

Maura L Boerio
Abhijnan Chattopadhyay
Xue-Yan Duan
Aamuktha Karla
Ernesto Calderon Martinez
Amelie Pinard
Andrew K Morse
Darshan Reddy
Sree Dharma
Walter Velasco-Torrez
Julien Marcadier
Siddharth K Prakash
Sherene Shalhub
Julie De Backer
Richmond Jeremy
Shaine A Morris
Anji T Yetman
Alan C Braverman
Dianna M Milewicz

Language

English

Publication Date

2-1-2026

Journal

Circulation: Genomic and Precision Medicine

DOI

10.1161/CIRCGEN.125.005169

PMID

41582817

PMCID

PMC12841933

PubMedCentral® Posted Date

1-26-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells.

Methods: The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as other recurrent ACTA2 missense variants, were individually expressed in Acta2-/- smooth muscle cells, and transcript and protein levels, HSF1 (heat shock factor 1) activation, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) expression and activity, cholesteryl ester levels, and downstream smooth muscle cell phenotypic modulation were assessed.

Results: Early onset ASCVD included coronary artery disease, peripheral vascular disease, and atherosclerotic plaques identified by imaging in the arch, descending, or abdominal aorta, along with the celiac, iliac, renal, or vertebral arteries. Twelve ACTA2 variants were identified to be associated with early onset ASCVD. Early onset ASCVD was correlated with HSF1 activation (P=0.035), cellular cholesteryl ester levels (P=0.0031), and having one family member with the specific ACTA2 pathogenic variant who had early onset ASCVD (P=0.0001).

Conclusions: Assays assessing the molecular mechanism that leads to early onset ASCVD can identify which ACTA2 pathogenic variants will trigger this condition. Ultimately, this information informs precision medical care for individuals with ACTA2 pathogenic variants, with the ultimate goal of preventing thoracic aortic disease and ASCVD.

Keywords

Humans, Atherosclerosis, Actins, Myocytes, Smooth Muscle, Heat Shock Transcription Factors, Cholesterol, Male, Female, Middle Aged, Age of Onset, Mutation, Missense, actins, atherosclerosis, cholesterol esters, coronary artery disease, heat shock transcription factors

Published Open-Access

yes

Recommended Citation

Boerio, Maura L; Chattopadhyay, Abhijnan; Duan, Xue-Yan; et al., "ACTA2 Pathogenic Variants Activating Heat Shock Factor 1 and Increasing Cholesterol Biosynthesis in Smooth Muscle Cells Predispose to Early Onset Atherosclerosis" (2026). Faculty, Staff and Student Publications. 6263.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6263