Abstract 350: Inhibition of IGF-1 Signaling Increases Serum Cholesterol and Plaque Burden in ApoE Knockout Mice but Promotes a Stable Plaque Phenotype

Abstract

Insulin like growth factor-1 (IGF-1) has been shown to have a prominent effect on smooth muscle cell proliferation, migration and apoptosis. We and others have previously shown that inhibition of IGF-1 related signaling can attenuate intimal hyperplasia by attenuating smooth muscle cell proliferation and promoting apoptosis after vascular injury. We hypothesized with support from preliminary work in our laboratory that IGF-1 inhibition will decrease atherosclerosis burden, but may negatively affect plaque stability by increasing SMC apoptosis. Picropodophyllin(PPP) is a specific inhibitor of the IGF-1 receptor phosphorylation and is currently under development as an anti-cancer drug. The aim of this study was to study the short and long term effects of IGF-1 inhibition using PPP in ApoE deficient mice Methods and Results 12 week old Apo E deficient mice (n=64) were treated with an oral preparation of PPP or vehicle (controls) for a period of 10 and 18 weeks. Blood samples were collected before sacrifice and aortas, brachiocephalic trunks and liver samples harvested. Semi-quantitative analysis of the aortic and brachiocephalic trunks using Sudan IV enface staining showed an increase in plaque burden and was significant after 18 weeks. There were no significant differences in weight, serum creatinine, albumin or glucose levels between the two groups. However, we noted 18% lower levels of IGF-1, doubled levels of growth hormone, 30% increase in serum cholesterol levels in the PPP treated group (p<0.05). RT-PCR analysis showed a 38% decrease in LDL receptor expression in the liver in the PPP group. Further immunohistochemical analysis of the plaques showed more fibrosis and lower cholesterol in the sections of the brachiocephalic trunks of the PPP group. Conclusion In contrast to our hypothesis, PPP treatment increased plaque burden but led to plaques with a more stable phenotype. The proposed mechanism is via an increase in serum cholesterol, however further work has to be performed to confirm the pathways involved. In summary, our results suggest that the effects of inhibition of IGF-1R phosphorylation in atherosclerotic animals cannot be extrapolated from results in healthy subjects and has to be considered when designing drugs in the future.