Abstract 17068: IGFBP-1 Increases Endothelial Nitric Oxide via PI-3-K Activation and Rescues Vascular Function in Murine Models of Endothelial Dysfunction
Background: Insulin resistant individuals, who are at elevated CV risk, have reduced concentrations of the carrier protein Insulin-like Growth Factor Binding Protein-1 (IGFBP-1). In obese mice with endothelial dysfunction IGFBP-1 concentrations decline, while we have previously demonstrated favourable influences on endothelial function of transgenic IGFBP-1 over-expression in mice. We speculated that restoring IGFBP-1 concentrations may be protective in models of endothelial dysfunction, and tested the mechanism by which IGFBP-1 increases endothelial NO.
Methods: Male IGFBP-1 transgenic C57Bl/6 mice and littermate controls were tested in 2 settings of endothelial dysfunction: (i) diet-induced obesity (DIO) and; (ii) crossing with heterozygous insulin receptor knockout mice (IRKO). Cardiovascular function was assessed by tail cuff blood pressure, aortic ser1177eNOS phosphorylation following insulin bolus, and aortic vasomotion ex vivo. To dissect the mechanisms, complementary in vitro studies were conducted with exogenous IGFBP−1. Thus after incubation with IGFBP-1, we tested NO-dependent vasomotion in isolated aorta (organbath), and eNOS activity and ser1177phospho-eNOS expression in cultured human endothelial cells (arginine-citrulline conversion assay, western blot and immunofluorescence). Upstream signalling intermediaries were probed by specific inhibitors.
Results: DIO and IRKO mice predictably developed endothelial dysfunction and hypertension. In contrast, IGFBP1 transgenic mice with DIO or IRKO had preserved endothelial function, normal blood pressure, and improved gluco-regulation in DIO despite equal weight gain. 500ng/ml IGFBP-1 significantly increased expression of phospho-eNOS, eNOS activity, and endothelial NO generation via PI-3-kinase activation. No IGF-I was present in these assays, and IGFBP-1 also increased endothelial NO generation in aorta isolated from mice with homozygous knockout of the endothelial IGF-receptor. Implications: IGFBP-1 over-expression rescued vascular function and reduces CV risk in both obese and non-obese models of endothelial dysfunction, via a PI-3-kinase dependent generation of NO. These data support a critical and direct role for IGFBP-1 in vascular biology.
- © 2010 by American Heart Association, Inc.