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Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model
Published on: June 3, 2020
IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice.
V Hillestad1, E K S Espe, F Cero
1Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Neutralizing interleukin-18 (IL-18) with IL-18 binding protein (IL-18BP) during alveolar hypoxia improved left ventricular diastolic function in mice. This treatment also helped prevent right ventricular hypertrophy, suggesting IL-18 plays a role in hypoxia-induced cardiac dysfunction.
Area of Science:
- Cardiology
- Pulmonary Medicine
- Immunology
Background:
- Pulmonary diseases are linked to left ventricular (LV) diastolic dysfunction.
- Alveolar hypoxia induces LV diastolic dysfunction and elevates circulating interleukin-18 (IL-18).
- IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18.
Purpose of the Study:
- To investigate if neutralizing IL-18 with IL-18BP during alveolar hypoxia improves LV diastolic function.
- To assess the impact of IL-18 neutralization on cardiac morphology and molecular changes.
Main Methods:
- Mice were exposed to hypoxia (10% oxygen) for 2 weeks, treated with IL-18BP or vehicle.
- Cardiac function and morphology were assessed using echocardiography, intraventricular pressure measurements, and MRI.
- Molecular changes in the heart and circulating cytokines were analyzed via real-time PCR, Western blotting, and ELISA.
Main Results:
- Hypoxia induced LV diastolic dysfunction, evidenced by prolonged isovolumic relaxation time constant (τ).
- IL-18BP treatment significantly improved relaxation, reducing τ towards control values.
- IL-18BP treatment normalized decreased levels of phosphorylated phospholamban (P-PLB) and reduced right ventricular (RV) wall thickness increase.
Conclusions:
- Neutralization of IL-18 during alveolar hypoxia improves LV diastolic function.
- IL-18 neutralization partly prevents RV hypertrophy in hypoxic conditions.
- IL-18 appears to regulate calcium-handling proteins involved in hypoxia-induced diastolic dysfunction.
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