Abstract 13977: Insulin-Like Growth Factor Binding Protein 7 is Associated With Development of Cell Senescence and Progression of Coronary Atherosclerosis

Abstract

Introduction: Cellular senescence, an irreversible cell cycle arrest, has been associated with atherosclerosis. Senescent cells (SC) secrete proinflammatory molecules contributing to disease progression. Insulin-like growth factor binding protein 7 (IGFBP7) binds IGF-1 and also interacts with IGF-1 receptor, suppressing intracellular IGF-1 signaling. IGFBP7 has been linked to heart failure-associated cell senescence. Hypothesis: We hypothesize that SC secrete IGFBP7, and IGFBP7 contributes to atherogenesis. Methods: Premature cell senescence was induced by treatment of smooth muscle cells (SMC) with H2O2. IGFBP7 levels were measured by immunoblotting of cell lysates and conditioned media (CM) and by immunohistochemistry in Apoe-null mice and in Rapacz hypercholesterolemic pigs. Binding of IGFBP7 with IGF-1 receptor was quantified by proximity ligation assay. Results: H2O2-treated SMC have marked increase in expression of the senescence markers beta-galactosidase (SA-βGal) and γH2A.X, and 3-fold (P<0.05) increase in IGFBP7 in cell CM. Abundant senescent SMC (αSMA + /SA-βGal + ) were detected in fibrous cap’s plaque in murine innominate artery and these cells had increased IGFBP7 compared to SMC in the vascular media. Increased IGFBP7 levels (1.8-fold increase, P<0.05) were also detected in porcine coronary plaque and IGFBP7 upregulation correlated with elevated IGFBP7/IGF-1 receptor binding. These data suggest a mechanistic link between senescence, IGFBP7 upregulation and atherogenesis. SMC were incubated with CM from senescent SMC (or non-senescent controls) to determine if SC-secreted IGFBP7 inhibits IGF-1 signaling. Preincubation with CM from SC inhibited IGF-1-induced Akt phosphorylation, however co-incubation with anti-IGFBP7 antibody reversed this effect, indicating that IGFBP7 in the CM mediates the inhibitory effect on IGF-1 signaling. Conclusions: We have shown that SMC senescence induced IGFBP7 and that high IGFBP7 levels were associated with senescent SMC in the atherosclerotic plaque. IGFBP7 inhibits IGF-1 signaling in vitro and binds IGF-1 receptor in plaque SMC. Our results suggest a novel role of IGFBP7 in senescence and in atherogenesis and identify IGFBP7 as a potential target for anti-atherogenic therapy.