Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure

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.

Mapping the aetiological foundations of the heart failure spectrum using human genetics

“…KLF12 is a transcription factor that is upstream of p53 and p21 ( CDKN1A ); methylation of the KFL12 transcription factor binding motif has been identified as a mechanism for LMNA cardiomyopathy 42 . In contrast to prior reports, we did not observe differential expression of IGFBP7 in cardiomyocytes from failing hearts 37 .…”

“…IGFBP7 , a circulating anti-angiogenic factor produced by the kidney and the vasculature, was prioritised within a ni-HFpEF locus. IGFBP7 was recently reported to stimulate cardiomyocyte senescence and cardiac remodelling 37 . Pathways related to cardiac arrhythmia, including regulation of cardiac muscle contraction by calcium ion sensing and cell communication by electrical coupling were specifically enriched for ni-HF.…”

“…IGFBP7 is synthesised by the vasculature in response to tissue damage and may be an upstream driver of cell cycle arrest, fibrosis, and vascular rarefaction that are observed in HFpEF. IGFBP7 is an established clinical biomarker of acute renal failure and may represent a target for novel therapeutics 37,58 .…”

Insulin‐like growth factor binding protein‐7 concentrations in chronic heart failure: Results from the EMPEROR programme

“…9 Furthermore, RNA-mediated silencing of IGFBP7 or neutralization with monoclonal antibodies blocked the actions of IGFBP7 on FOXO3a signalling and mitigated pressure overload-induced HF. 29 marker of renal stress and a potential mediator of the progression of chronic kidney disease. 30 These results implicate IGFBP7 as a potential target for future therapies to slow the progression of HF and nephropathy.…”

A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging

“…Several SASP factors have already been linked to worse prognosis in cardiovascular disease. Examples are IGFBP7 156 , 157 , interleukin-6 (IL-6) 158 , 159 , and GDF-15 65 , 160 . Patients with chronic heart failure (BIOSTAT-CHF) with elevated levels of IGFBP7 showed a 44% (HR = 1.44 [CI 1.23–1.70], p < 0.001) increase in combined adverse endpoints 156 .…”