Background/aims: Aortic valve stenosis is a common and serious disease for which there is currently no effective drug therapy. Sphingosine-1-phosphate (S1P) is known as a key regulator of osteogenesis, where it controls cellular remodeling processes. It is not yet clear whether S1P triggers similar mechanisms in the aortic valve, thereby contributing to calcification. The influence of S1P on the development of aortic valve stenosis and the possible protective effects pharmacological modulation were investigated.
Methods: The influence of different S1P levels on the progression of aortic valve stenosis was investigated in genetically and pharmacologically modified mouse models. Stenosis was induced using a wire injury model. Echocardiographic measurements of pump function, ejection fraction, flow velocity, valve opening area and left ventricular dimensions were performed at defined time points (preoperatively and after 4, 8 and 12 weeks). Histological analyses of calcification, PCR analyses of the heart failure markers BNP and ANP and ELISA measurements of OPG and RANKL were then performed.
Results: Elevated S1P levels exacerbated aortic valve stenosis and led to more severe impairment of cardiac function, while reduced S1P levels or an S1PR2 defect attenuated the disease. Higher S1P levels were also associated with increased expression of heart failure markers BNP and ANP. RANKL plasma concentration was elevated at low S1P levels and decreased under DOP therapy (high S1P), while OPG levels increased under DOP. S1PR2-deficient mice showed lower flow velocity, lower pressure gradients, larger valve opening areas, and better heart function compared to wild-type mice. Under DOP therapy, these animals did not show any deterioration in AVD. S1PR2 inhibition with JTE-013 had a protective effect against calcification, whereas the addition of the S1P analogue FTY-720 had no effect. Pharmacological S1PR2 inhibition after induction of stenosis prevented disease progression and its cardiac consequences.
Conclusion: S1P controls cellular remodeling processes in the aortic valve and promotes disease progression. Inhibition of S1PR2 represents a potentially promising therapeutic approach to prevent the progression of aortic valve stenosis and could be relevant for both preventive and secondary preventive therapies in the future.
