Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure
Liyong Zhang1, David Smyth1, Mohammad Al-Khalaf1
1University of Ottawa Heart Institute, Ottawa, ON, Canada.
Insights
Insulin-like growth factor-binding protein 7 (IGFBP7) exacerbates heart failure (HF) by promoting cardiac senescence and inflammation. Targeting IGFBP7 offers a potential therapeutic strategy for age-related cardiac decline in HF patients.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Aging Research
Background:
- Heart failure (HF) represents a growing global cardiovascular health crisis, particularly impacting aging populations.
- Age-related cardiac dysfunction necessitates novel, precise therapeutic interventions.
- Chronic inflammation is a key driver of HF progression.
Purpose of the Study:
- To investigate the role of Insulin-like growth factor-binding protein 7 (IGFBP7) in the pathogenesis of heart failure.
- To explore IGFBP7 as a potential therapeutic target for age-related cardiac decline.
Main Methods:
- Analysis of IGFBP7 expression in human HF patients and a pressure overload mouse model.
- Investigating the effects of Igfbp7 deficiency and knockdown on cardiac function, inflammation, fibrosis, and senescence in mice.
- Utilizing AAV9-shRNA for targeted cardiac myocyte Igfbp7 knockdown.
- Employing antibody-mediated IGFBP7 neutralization in vivo.
Main Results:
- Cardiac and blood IGFBP7 levels were significantly elevated in HF patients and models.
- Igfbp7 deficiency attenuated cardiac dysfunction, inflammation, fibrosis, and senescence in a mouse HF model.
- IGFBP7 was found to promote cardiac senescence via suppression of FOXO3a, impairing DNA repair and ROS detoxification.
- Myocardial IGFBP7 directly influences pathological cardiac remodeling, and its neutralization reversed HF progression in mice.
Conclusions:
- IGFBP7 plays a direct role in accelerating heart failure progression by promoting cardiac senescence and inflammation.
- Targeting IGFBP7 and its associated senescence pathways presents a promising therapeutic avenue for 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.
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