Fig. 5: IGFBP7 promotes cardiac senescence by simulating IGF-1R/IR-dependent suppression of FOXO3a.
From: Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure
Igfbp7−/− and WT mice were subjected to TAC or sham surgery and analyzed 8 weeks after the operation. Representative immunoblotting (a–d) and quantification (g) for activation of IGF-1 receptor (a), shown by the ratio of phosphor-IGF-1R to total IGF-1R; IRS-1 (b), shown by the ratio of phosphor-IRS-1 to total IRS-1; its downstream activation of Akt (c), shown by the ratio of phospho-Akt to total Akt; and inactivation of FoxO3a transcription factor (d), shown by the ratio of phospho-FoxO3a and total FoxO3a to Gapdh. Gapdh was used as loading control. Representative immunoblotting (e–f) and quantification (g) show that downregulation of FoxO3a targets Ddb1 in WT mouse hearts (e), and acetylation of Sod2 (Sod2K68A), as shown by Sod2K68Ac to total Sod2, was upregulated in WT TAC hearts (f). Total protein was used as loading control. Protein expression is shown as fold change against WT sham group (n = 3 for pIgf-1Rb, pIrs1318, pAkt308, Ddb1 and Sod2k68Ac over one experiment; n = 6 for pIrs1S612 over two independent experiments; and n = 9 for pAktS473, pFoxO3aS253 and total FoxO3a over three independent experiments). h, Increased catalase activity in Igfbp7−/− TAC hearts as measured by catalase activity assay (n = 5 per group). i, Relative expression of key FoxO3a-targeted genes Gadd45a, Ddb1, Sod2, Cad and cdkn1b in heart samples 8 weeks after surgery. Gene expression is shown as fold change against WT sham group (n = 9 per group over three independent experiments). In all panels, error bars represent s.e.m. One-way ANOVA with Bonferroni correction for multiple comparisons was used to calculate P values. j, Diagram shows proposed IGFBP7 action in the stress myocardium.
