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

The molecular pathway linking misfolded 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.