Pharmacological clearance of senescent cells reverses HFpEF hallmarks by decreasing inflammation, endothelial dysfunction and cardiac fibrosis
Abstract Aging and chronic inflammation are associated with the development of heart failure with preserved ejection fraction (HFpEF). However, cellular senescence as a potential mechanistic link between both events and its pathophysiological and therapeutic role were yet unexplored. Here we show that ZSF1-obese rats, a model of cardiometabolic HFpEF, have exacerbated systemic inflammation and endothelial damage compared to ZSF1-lean littermates. In addition, ZSF1-obese rats accumulated immune and endothelial senescent cells in the peripheral blood and myocardium. Accordingly, the frequency of circulating senescent leukocytes associated with markers of disease severity in HFpEF patients. Notably, systemic treatment of ZSF1-obese rats with Navitoclax, a BCL-2 family inhibitor, reduced senescent cell burden, decreased circulating B-type natriuretic peptide levels, and attenuated inflammation, vascular remodeling and cardiac fibrosis. Our findings advance cellular senescence as a key mechanistic pathway leading to HFpEF and provide proof-of-concept evidence that senolytics are a promising treatment for this disease..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
ResearchSquare.com - (2021) vom: 10. Aug. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Silva, Elsa [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-624229/v1 |
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| 520 | |a Abstract Aging and chronic inflammation are associated with the development of heart failure with preserved ejection fraction (HFpEF). However, cellular senescence as a potential mechanistic link between both events and its pathophysiological and therapeutic role were yet unexplored. Here we show that ZSF1-obese rats, a model of cardiometabolic HFpEF, have exacerbated systemic inflammation and endothelial damage compared to ZSF1-lean littermates. In addition, ZSF1-obese rats accumulated immune and endothelial senescent cells in the peripheral blood and myocardium. Accordingly, the frequency of circulating senescent leukocytes associated with markers of disease severity in HFpEF patients. Notably, systemic treatment of ZSF1-obese rats with Navitoclax, a BCL-2 family inhibitor, reduced senescent cell burden, decreased circulating B-type natriuretic peptide levels, and attenuated inflammation, vascular remodeling and cardiac fibrosis. Our findings advance cellular senescence as a key mechanistic pathway leading to HFpEF and provide proof-of-concept evidence that senolytics are a promising treatment for this disease. | ||
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