Insulin-Like Growth Factor-1 and Atherosclerosis

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PROJECT SUMMARY / ABSTRACT Coronary heart disease is a primary contributor to cardiovascular disease worldwide. Despite optimal treatment many patients remain vulnerable to ischemic events. While small animal models have proven extraordinarily effective at exploring mechanisms, studies in large animal models are critically needed, as a bridge between rodent studies and human trials, and to develop new therapies. We have shown that insulin-like growth factor-1 (IGF-1) reduces atherosclerotic burden and promotes features of plaque stability in Apoe-/- mice and in Rapacz swine with familial hypercholesterolemia (FH pigs). Our novel findings indicate that IGF-1 reduces the number of senescent cells, including senescent SMC-like and MF-like cells in pig coronary atherosclerotic plaques, in particular in the fibrous cap (FC). Cellular senescence is thought to play a vital role in aging and in the development of chronic disease. However, the relation between IGF-1, cell senescence and atherosclerotic disease is virtually unknown. Senescent cells contribute to atherogenesis and fibrous cap thinning in mouse models, but there is no information on the causal role of cell senescence in atherogenesis in large animal models or in humans. Using scRNA-seq analysis of aortas from Apoe-/- mice and spatial transcriptomics analysis of porcine plaque we show high-level expression of the senescence-associated secretory phenotype (SASP) factor IGF binding Protein-7 (IGFBP7), an IGF-1 inhibitor, in the fibrous cap, primarily localized to SMC-like cells, particularly fibromyocytes. Elevated senescence scores are strongly associated with fibromyocytes and high IGFBP7 expression. We hypothesize that senescent cells inhibit IGF-1 signaling and that SASP-induced IGF-1 resistance reduces anti-atherosclerotic effects of IGF-1. Our data shows that conditioned medium from senescent cultured SMC inhibits IGF1R signaling in SMC, an effect reversed by anti-IGFBP7 antibody. Our overall goal is to demonstrate that removal of senescent cells using a senolytic, ABT263, will reduce atherosclerosis in a large animal model and potentiate anti-atherosclerotic effects of IGF-I. We will also demonstrate the role of IGFBP7 in IGF-1 resistance using a loss-of-function murine model, and further explore mechanisms using in vitro studies. Specific Aim 1: Test the hypothesis that clearance of senescent cells using a senolytic in a large animal model of atherosclerosis will reduce atherosclerotic burden and potentiate IGF-1 ability to reduce atherosclerotic burden and promote plaque stability. scRNA-seq, spatial transcriptomics, multi-marker histology, and laser capture microdissection (LCM) will be used to dissect mechanisms. Specific Aim 2: Specific Aim 2: Demonstrate that genetic deprivation of IGFBP7 in SMC-like cells enhances anti-atherosclerosis effects of IGF-1. We will use SMC-selective IGFBP7-deficient mice, scRNA- seq analysis and in vitro models to dissect mechanisms.