Impairment of the adaptive SK1/S1P cardioprotective axis in chronic heart failure.

Background: Over the last decades, the sphingosine kinase 1 (SK1)/sphingosine1-phosphate (S1P) axis has attracted increasing attention in cardiovascular research due to its effects under acute or chronic stress conditions. Despite this, the specific role of this molecular pathway in human heart failure (HF) remains poorly defined. Likewise, the potential of circulating S1P as a biomarker of HF has not been fully established. Methods and results: To this aim, we enrolled 28 patients with HF and 16 non-HF controls. We observed that serum S1P levels were significantly reduced in HF patients compared with controls, and S1P was positively associated with left ventricular ejection fraction (EF). Further, ROC analysis demonstrated a moderate discriminatory capacity of S1P for HF. However, this relationship was partly influenced by age, as S1P levels were inversely correlated with age. Among laboratory parameters, circulating S1P levels were inversely associated with serum creatinine, suggesting a potential link between S1P signaling and cardiorenal dysfunction. Next, In differentiated human AC16 cardiomyocytes, acute β-adrenergic stimulation with isoproterenol increased SK1 and PCNA expression, whereas prolonged stimulation reduced SK1 levels, indicating a biphasic regulation of the SK1/S1P axis under sustained adrenergic stress. Similarly, hypoxic insult in AC16 cells resulted in a significant reduction in SK1 levels and increased p53 levels. Finally, in AC16 incubated withwith human blood serum from HF patients we observed a robust reduction in SK1 compared with cells incubated with control serum. Conclusions: In conclusion, this study supports SK1/S1P axis as an adaptive cardioprotective mechanism activated during acute stress that becomes impaired in chronic HF-related stress. Although the association between circulating S1P and myocardial SK1 requires further investigation, reduced circulating S1P was consistently associated with HF and impaired cardiac function, supporting its potential value as a biomarker and highlighting the SK1/S1P axis as a promising therapeutic target.