Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure
Nature Cardiovascular Research(2022)
Abstract
Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model. In a pressure overload mouse HF model, Igfbp7 deficiency attenuated cardiac dysfunction by reducing cardiac inflammatory injury, tissue fibrosis and cellular senescence. IGFBP7 promoted cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and reactive oxygen species (ROS) detoxification, thereby accelerating the progression of HF. In vivo, AAV9-shRNA-mediated cardiac myocyte Igfbp7 knockdown indicated that myocardial IGFBP7 directly regulates pathological cardiac remodeling. Moreover, antibody-mediated IGFBP7 neutralization in vivo reversed IGFBP7-induced suppression of FOXO3a, restored DNA repair and ROS detoxification signals and attenuated pressure-overload-induced HF in mice. Consequently, selectively targeting IGFBP7-regulated senescence pathways may have broad therapeutic potential for HF. Zhang et al. show increased blood concentration of IGFBP7 in patients and a mouse model with heart failure (HF). IGFBP7 promotes cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, and Igfbp7 deficiency or inhibition attenuates cardiac dysfunction in a pressure overload mouse HF model, suggesting that therapeutic targeting of IGFBP7 might be promising for the treatment of HF.
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Key words
Ageing,Heart failure,Prognostic markers,Cardiovascular Biology
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