Targeted modulation of sphingolipid signaling to inhibit the progression of aortic valve disease

Abstract Background Aortic valve disease (AVD) is linked to significant mortality and morbidity. Currently, there is no pharmacological treatment to halt the progression of AVD. Given that valve calcification is a defining feature of AVD and sphingosine-1-phosphate (S1P) is crucial in osteogenic signaling, we investigated the role of S1P signaling in aortic stenosis (AS). Methods The progression of AVD and its impact on cardiac function were studied in a murine model of wire injury-induced AVD, with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P levels were measured using LC-MS. The calcification of valvular interstitial cells (VICs) and their response to biomechanical stress were assessed in the context of S1P signaling. S1P levels in human explanted aortic valves from patients undergoing aortic valve replacement, as well as CMR imaging, were also analyzed using LC-MS. Results Increasing S1P levels in mice with injury-induced AVD through pharmacological inhibition of its sole degrading enzyme, S1P lyase, significantly accelerated AVD progression and impaired cardiac function, closely mimicking human disease. In contrast, reduced S1P levels due to sphingosine kinase 1 (SphK1) deficiency strongly mitigated AVD progression. We identified S1P/S1P receptor 2 (S1PR2) signalling as the key driver of the harmful effects of S1P, as mice lacking S1PR2 were protected from AVD progression and its exacerbation by elevated S1P. Notably, pharmacological inhibition of S1PR2 administered after wire injury effectively prevented AVD development. Mechanistically, biomechanical stretch triggered S1P production by SphK1 in human VICs, as evidenced by C17-S1P generation. S1P/S1PR2 signaling then induced osteoblastic differentiation and calcification of VICs through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress exhibited higher S1P content and increased SphK1 expression. Conclusions Elevated systemic or local S1P levels contribute to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors could provide viable pharmacological strategies for human AVD, offering potential for prophylactic treatment, disease modification, or prevention of relapse.