Introduction Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal, accelerated-aging disease caused by a mutation in the nuclear envelope protein Lamin A. The resulting mutant protein, progerin, accumulates on the nuclear envelope, causing nuclear blebbing, altered gene expression, and other cellular defects. The primary pathology of HGPS is atherosclerosis, leading to stroke or heart attack. Given that atherosclerosis generally begins with endothelial dysfunction, we examined whether the HGPS endothelium has an altered genetic response to shear stress, contributing to atherogenesis. Methods We exposed HGPS and healthy iPSC-derived endothelial cells (viECs) to steady laminar shear stress at 12 dyn/cm 2 in a parallel-plate flow chamber. We examined morphology changes, differential gene expression (DE) via RNA-seq, and Gene Set Enrichment Analysis (GSEA) after 24 h. Results Elongation after flow is impaired in HGPS viECs compared with healthy viECs. DE analysis showed fewer significant DE genes and a lower magnitude of gene expression change after flow in HGPS compared with healthy viECs. GSEA identified differences in the gene sets altered by flow-induced DE, including Cholesterol Homeostasis, which was overrepresented in HGPS viECs. LGALS3, encoding the atherosclerosis marker galectin-3, was a main driver of this overrepresentation. RT-PCR confirmed LGALS3 is robustly upregulated in HGPS viECs compared with healthy viECs after flow. Treatment with an adenine base editor correcting the HGPS mutation restored LGALS3 expression to healthy levels. Conclusion These observations indicate that HGPS ECs have an aberrant molecular response to atheroprotective shear stress, including impaired elongation and upregulation of the pro-inflammatory gene LGALS3, which contributes to atherogenesis in HGPS patients.
Kennedy et al. (Tue,) studied this question.