Therapeutic CFTR Correction Normalizes Systemic and Lung-Specific S1P Level Alterations Associated with Heart Failure

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Molecular Biology

Background:

• Heart failure (HF) is a major global cause of mortality.
• Sphingosine-1-phosphate (S1P) signaling is implicated in HF and associated organ damage.
• Cystic fibrosis transmembrane regulator (CFTR) controls intracellular S1P degradation, and HF downregulates CFTR.

Purpose of the Study:

• To investigate the relationship between S1P and CFTR expression in the HF lung.
• To determine if CFTR alterations in HF affect systemic and tissue-specific S1P concentrations.
• To evaluate the therapeutic potential of CFTR correction in HF-associated inflammation.

Main Methods:

• Myocardial infarction was induced in mice to model HF.
• HF mice were treated with the CFTR corrector C18.
• Pulmonary and systemic S1P levels, CFTR expression, and immune cell profiles were analyzed using Western blotting, mass spectrometry, flow cytometry, and qPCR.

Main Results:

• HF mice exhibited decreased pulmonary CFTR expression, elevated pulmonary S1P concentrations, and a pro-inflammatory lung state.
• HF was associated with increased plasma S1P levels and higher S1P receptor 1-positive immune cells in the spleen.
• C18 treatment normalized pulmonary CFTR expression, reduced S1P levels, and attenuated lung inflammation in HF mice.

Conclusions:

• HF is linked to reduced pulmonary CFTR expression and subsequent increases in S1P.
• The CFTR-S1P axis plays a significant role in HF-associated systemic and pulmonary inflammation.
• CFTR correction represents a potential therapeutic strategy for managing inflammation in heart failure.