Insulin-like growth factor I reduces coronary atherosclerosis in pigs with familial hypercholesterolemia

To investigate effects of IGF-1 on human-like coronary atherosclerosis we used high fat diet-fed Rapacz pigs with familial hypercholesterolemia (FH pigs). We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. IGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (data obtained by serial intravascular ultrasound) and lesion cross-sectional area (post-mortem histology). IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. ST analysis revealed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis. FH pigs were fed with high-fat diet and received daily injections of IGF-1 or saline (control) for 6 months. A total 4 cryosections of right coronary artery (RCA) were obtained from female FH pigs (N=2, IGF-1-treated pigs, N=2, saline-treated pigs, control) and used for spatial transcriptomics (ST). Section imaging, RNA extraction, cDNA library preparation and sequencing were performed in according to the ST’s manufacturer (Visium/10X genomics) recommendations.