Abstract 13545: Differential Requirement for Nitric Oxide in Insulin-Like Growth Factor I-Induced Anti-Apoptotic, Anti-Oxidant and Anti-Atherosclerotic Effects
We have shown that insulin like-growth factor I (IGF-1) suppresses atherosclerosis and increases features of plaque stability in Apoe-/- mice and this effect correlated with reduced vascular superoxides and activation of the major nitric oxide (NO)-producing enzyme endothelial NO synthase. To determine if NO is required for IGF-1-induced anti-oxidant and anti-atherogenic effects, Apoe-/- mice were infused with IGF-1 (1.5 mg/kg) or saline for 12w and treated with the pan-NO synthase inhibitor L-NAME, or D-NAME (control). IGF-1 increased urinary nitrates/nitrites, an index of systemic NO bioavailability, in the D-NAME group (IGF-1: 23.6±3.4 vs. saline: 14.1±1.3 mol/d/g, P<0.05), and L-NAME blocked this effect (IGF-1: 11.7±1.3 vs. saline: 12.8±0.8 mol/d/g, P=NS). IGF-1 reduced atherosclerotic plaque burden in both the D-NAME (37±5% decrease, P<0.05), and L-NAME group (39±5% reduction, P<0.05). Similarly, total plaque cell apoptosis was reduced by IGF-1 in both D-NAME and L-NAME groups (37±5% and 30±4% decrease, respectively, P<0.05, TUNEL assay) and plaque smooth muscle cell (SMC) levels were upregulated by IGF-1 in both D-NAME and L-NAME groups (2.1±0.2- and 1.8±0.2-fold increase, respectively, P<0.05, immunohistochemistry (IHC), a-SM actin a/b). These data indicated that NO was not required for IGF-1 induced anti-atherogenic and anti-apoptotic effects. However, IGF-1 reduced plaque oxidative stress in the D-NAME group (IHC, N-tyrosine antibody: 54±6% decrease vs. saline, P<0.05; 8-oxo-dG antibody: 52±5% decrease, P<0.05), and this effect was markedly blunted by L-NAME indicating that IGF-1's anti-oxidant effect was NO-dependent. Microarray analysis revealed that IGF-1 decreased aortic TNF-a and lipoprotein lipase (LPL, an enzyme that increases lipid uptake by macrophages)expression in the D-NAME group. IGF-1 reduction of TNF-a but not LPL was completely blocked by L-NAME. In summary, IGF-1 increases NO levels, suppresses oxidative stress and downregulates TNF-a in Apoe-/- mice, however these mechanisms do not mediate the IGF-1-induced anti-atherogenic effect. Because IGF-1-induced anti-apoptotic effects and LPL downregulation are NO-independent they may play a major role in mediating IGF-1's anti-atherosclerotic effects.
- © 2011 by American Heart Association, Inc.