Abstract
Heart failure (HF) is among the main causes of death worldwide. Alterations of sphingosine-1-phosphate (S1P) signaling have been linked to HF as well as to target organ damage that is often associated with HF. S1P’s availability is controlled by the cystic fibrosis transmembrane regulator (CFTR), which acts as a critical bottleneck for intracellular S1P degradation. HF induces CFTR downregulation in cells, tissues and organs, including the lung. Whether CFTR alterations during HF also affect systemic and tissue-specific S1P concentrations has not been investigated. Here, we set out to study the relationship between S1P and CFTR expression in the HF lung. Mice with HF, induced by myocardial infarction, were treated with the CFTR corrector compound C18 starting ten weeks post-myocardial infarction for two consecutive weeks. CFTR expression, S1P concentrations, and immune cell frequencies were determined in vehicle- and C18-treated HF mice and sham controls using Western blotting, flow cytometry, mass spectrometry, and qPCR. HF led to decreased pulmonary CFTR expression, which was accompanied by elevated S1P concentrations and a pro-inflammatory state in the lungs. Systemically, HF associated with higher S1P plasma levels compared to sham-operated controls and presented with higher S1P receptor 1-positive immune cells in the spleen. CFTR correction with C18 attenuated the HF-associated alterations in pulmonary CFTR expression and, hence, led to lower pulmonary S1P levels, which was accompanied by reduced lung inflammation. Collectively, these data suggest an important role for the CFTR-S1P axis in HF-mediated systemic and pulmonary inflammation.
Highlights
The bioactive sphingophospholipid sphingosine-1-phosphate (S1P) has been shown to control various cellular events relevant to cardiovascular disease (CVD), including immune cell chemotaxis [1], polarization and cytokine production [2,3,4,5], vascular responsiveness [6,7,8,9,10,11] and barrier function [12,13,14]
In a murine model of heart failure (HF) (i.e., 12-weeks post-myocardial infarction induced by permanent left anterior descending coronary artery ligation; average ejection fraction of 46.7 ± 7.5%), we observed significantly reduced pulmonary cystic fibrosis transmembrane regulator (CFTR) protein expression (Figure 1a), which was accompanied by an elevation of overall pulmonary S1P levels (Figure 1b)
We tested whether therapeutic correction of CFTR expression in vivo affects pulmonary S1P levels by treating HF mice with the CFTR corrector compound C18, starting 10 weeks post-myocardial infarction (Figure 2)
Summary
The bioactive sphingophospholipid sphingosine-1-phosphate (S1P) has been shown to control various cellular events relevant to cardiovascular disease (CVD), including immune cell chemotaxis [1], polarization and cytokine production [2,3,4,5], vascular responsiveness [6,7,8,9,10,11] and barrier function [12,13,14]. The cystic fibrosis transmembrane regulator (CFTR) has, in particular, emerged as a key element for S1P degradation by mediating S1P import into vascular smooth muscle cells where it controls S1P effects on vascular responsiveness [25,26]. In experimental HF, elevated tumor necrosis factor alpha (TNF-α) levels are responsible for considerable reduction of membrane CFTR expression and, impaired S1P import. Therapeutic CFTR correction has been shown to mitigate acquired CFTR deregulation and HF-associated target organ damage [11], direct effects on systemic and tissue-specific S1P levels remain unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
