Impact of platelet and red blood cell secretome on the progression of calcific aortic valve disease

• Applicant: Privatdozent Dr. Amin Polzin
• Subject Area: Cardiology, Angiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573914768

The only current approach to aortic valve disease is close monitoring until AVD is considered as severe. After that, the patients proceed to interventional or surgical valve replacement. There are no pharmaceutic options to prevent progression of AVD. Hence, a druggable target to treat AVD progression is urgently needed. We recently identified sphingosine-1-phosphate (S1P) as promising target. Red blood cells and platelets store a large amount of S1P that can be released upon activation. We recently showed that aortic swirling blood flow in AVD leads to damage of RBCs and activation of platelets. Taken together, blocking S1P release from circulating cells in AVD seems promising. However, many open questions remain (i) does aortic swirling blood flow due to reduced valve orifice area lead to enhanced platelet reactivity, (ii) do RBC release S1P during their fragmentation in AVD, (iii) does activation/fragmentation of circulating cells lead to enhanced S1P concentrations at site of aortic valve, (iv) is targeting circulating cell associated S1P release a promising option in prevention of AVD progression? The overarching hypothesis of this project is that blocking the release of S1P from circulating RBCs and platelets prevents progression of AVD. To address this, we plan the following work program: In work package one, we will analyze the impact of S1P released by RBCs, platelets or endothelium on AVD progression. We will infuse S1P-rich platelets or RBCs in AVD mice to allow specific evaluation of target cell S1P and not ubiquitous enhanced S1P concentrations. We will use genetic modulated mice with enhanced platelet S1P concentrations (SphK1 deficient mice) and ex-vivo S1P loading of RBCs as previously described by our group. In addition, we will investigate if genetic deficiency of S1P transporter Mfsd2b on circulating cells or Spns2 on endothelial cells prevents AVD progression. In WP2, we will test if inhibition of S1P release by RBCs and platelets is a druggable target. We will apply inhibition of S1P release from platelets by hydrolysis of ADP and ATP using apyrase. This is of special interest, as it does not enhance bleeding events. Furthermore, we will apply phosphatidylserine-binding by annexin V to prevent S1P release from RBCs during AVD. This will be tested in cell-culture, ex-vivo platelet and RBC analyses and in murine AVD. In the translational WP3, we will analyze the S1P content of circulating blood cells and plasma in AVD patients. We will compare blood samples from the left ventricle and the aortic root to analyze the impact of increased sheer stress at level of the stenotic valve. In addition, we will investigate changes in RBCs membrane integrity via electron microscopy and platelet activation via flow cytometry. Furthermore, 4D Flow MRI-based computational fluid dynamics analysis will be applied. Taken together, this study will pave the road to prevention of progression of AVD by targeting red blood cells and platelets.

• DFG Programme: Research Grants