Key result
Specific ACTA2 variants are linked to early-onset ASCVD, correlating with HSF1 activation and cellular lipid accumulation.
Why the study?
A subset of ACTA2 pathogenic variants lead to early onset atherosclerotic cardiovascular disease, but the molecular mechanisms linking specific variants to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation remained to be elucidated.
Do specific ACTA2 pathogenic variants predispose to early onset ASCVD through HSF1 activation and increased cholesterol biosynthesis?
Observational
Yes
Do specific ACTA2 pathogenic variants predispose to early onset ASCVD through HSF1 activation and increased cholesterol biosynthesis?
p-value: p=0.035, 0.0031, 0.0001
Specific ACTA2 pathogenic variants trigger early-onset ASCVD via HSF1 activation and increased cholesterol biosynthesis, highlighting a potential pathway for variant-specific precision medicine.
ACTA2 p.R149C carriers warrant earlier ASCVD vigilance; leaves open variant-specific prevention strategies.
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.
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Boerio et al. (2026) conducted an observational in ACTA2 pathogenic variants and early onset atherosclerotic cardiovascular disease. ACTA2 pathogenic variants was evaluated on Correlation of early onset ASCVD with HSF1 activation, cellular cholesteryl ester levels, and family history (p=0.035, 0.0031, 0.0001). Specific ACTA2 pathogenic variants were associated with early onset ASCVD, correlating with HSF1 activation (P=0.035), cellular cholesteryl ester levels (P=0.0031), and family history (P=0.0001).
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