Abstract 16472: Specific Inactivation of Insulin-Like Growth Factor-1 Receptor in Endothelium of ApoE-/- Mice Increases Atherosclerotic Plaque Burden
Although IGF-1 infusion in ApoE-/- mice reduces atherosclerotic plaque burden via a nitric oxide-independent pathway the role of endothelial IGF-1 receptor (IGF-1R) signaling in atherogenesis is unknown. Mice with an endothelial-specific IGF-1R null mutation (VFIRKO mice) were generated by crossing mice overexpressing cadherin 5 promoter-driven Cre recombinase with floxed IGF-1R+/+/Apoe-/- (FIR) mice. 7 w old VFIRKO and FIR (control) mice (n=20) were fed with pro-atherogenic Western-type diet for 12 weeks. Endothelial-specific IGF-1R deletion did not alter circulating IGF-1 levels (VFIRKO/FIR, 307.6+15.0 vs. 300.7+12.6 ng/ml), mouse body weight (VFIRKO/FIR, 26.3+0.8 vs. 26.0+0.8 g), spleen weight (VFIRKO/FIR, 130.5+13.3 vs. 25.2+32.2 mg), plasma nitrate/nitrite levels (index of nitric oxide bioavailability, VFIRKO/FIR, 8.6+0.4 vs. 7.3+0.9 umol/L) and systolic blood pressure (VFIRKO/FIR, 112.8+4.1 vs. 113.0+3.9 mm Hg). However, VFIRKO mice had increased atherosclerotic lesion surface area as assessed by Oil Red O staining of en face aortas (VFIRKO/FIR, 7.7+0.5% vs. 5.1+0.4%, p<0.005), indicating that endothelial IGF-1R signaling is anti-atherogenic. To determine mechanisms we assessed potential anti-oxidant effects of IGF-1 on vascular endothelium. IGF-1 (100 ng/ml, 24h) markedly reduced oxidized LDL-induced ROS generation in human aortic endothelial cells (EC, 67±9% decrease vs. OxLDL alone, P<0.01, DCF assay). IGF-1 did not alter expression or activity of superoxide dismutase-1, 2 or catalase but markedly increased expression (2.6-fold at 24h, Western blot, P<0.01) and activity (IGF-1 24h, 21.2 ± 2.1 U/mg protein vs. control, 4.4±1.2 U/mg protein, P<0.01) of glutathione peroxidase (GPX-1), a crucial anti-oxidant enzyme. In summary, IGF-1 exerts potent anti-oxidant effects on the endothelium, likely via upregulation of GPX-1, and inhibition of endothelial IGF-1R signaling is pro-atherogenic. Taken together these data suggest that GPX-dependent endothelial ROS suppression might mediate IGF-1-induced atheroprotection.
- © 2012 by American Heart Association, Inc.