INSULIN-LIKE GROWTH FACTOR I REDUCES CORONARY ATHEROSCLEROSIS IN PIGS WITH FAMILIAL HYPERCHOLESTEROLEMIA

Abstract

ABSTRACTObjectiveAlthough murine models of coronary atherosclerotic disease (CAD) have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We tested IGF-1 effects in atherosclerotic FH pigs to consider use of IGF-1 to treat CAD in humans. FH pigs were administered with IGF-1 for 6 months. Atherosclerosis was quantified by serial intravascular ultrasound (IVUS) and histology, plaque composition - by immunohistochemistry. We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects.ResultsIGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (IVUS) and lesion cross-sectional area (histology). IGF-1 induced vascular hypertrophy and reduced circulating triglycerides, markers of systemic oxidative stress and pro-atherogenic CXCL12 chemokine levels. 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. IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis.ConclusionsIGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials. ST profiling of plaques provided novel insights into potential mechanisms.