Restoring cardioprotection via S1P-Enriched HDL in coronary artery disease

Background High-density lipoprotein (HDL) levels are linked to cardiovascular outcomes; however, clinical trials aiming to reduce cardiovascular risk by increasing HDL concentrations have largely been unsuccessful. This suggests that HDL functionality, rather than its quantity, plays a pivotal role in cardiovascular protection. In this study, we investigated whether HDL from patients with coronary artery disease (CAD) exhibits impaired lipoprotective function and explored potential strategies to restore HDL functionality. Methods We investigated HDL properties by transfer experiments. Human HDL from CAD patients and healthy individuals were applied to mice undergoing acute myocardial infarction (AMI) via transient open-chest LAD ligation. Furthermore, HDL composition was measured using targeted LC/MS analyses. Results HDL from healthy individuals substantially reduced infarct size and improved ejection fraction after murine AMI (IS: 42.8±7.1% vs. 33.3±4.7%; EF: 33.7±4.9% vs. 41.1±4.5%). In contrast, HDL from CAD patients did not (IS: 40.4±5.2%; EF: 32.3±7.8%; n vehicle = 36, n healthy HDL = 21, n CAD-HDL = 12). The cardioprotective effect of healthy HDL was also evident in analyses conducted 21 days after AMI (scar size: 29.7±8.3% vs. 14.6±7.8%; n vehicle = 4, n healthy HDL = 5, p=0.0269). BSA-loaded sphingosine-1-phosphate (S1P) also provided cardioprotection. This was not surprising, as S1P administration enhances HDL-S1P content withing minutes. However, in animals with HDL receptor SRBI deficiency, the cardioprotective effects of HDL and BSA-S1P were absent. Comprehensive LC/MS analyses provided a detailed characterization of HDL composition. We found that S1P content was significantly reduced in CAD-HDL as compared to healthy individuals (HDL-S1P: 209.3±33.8pmol/mg vs. 158.2±47.31pmol/mg; n healthy HDL = 21, n CAD-HDL = 13, p=0.0009). ApoM-HDL content was similar in both groups. Hence, the ability to bind S1P is still present in CAD-HDL. Next, we aimed to restore HDL dysfunction by S1P-loading. Indeed, applying this S1P-loaded HDL from CAD patients in AMI mice, led to similar lipoprotection as compared to healthy-HDL. Conclusion In conclusion, we here found that HDL of CAD patients lack S1P, leading to blunted HDL cardioprotection. We found an option to restore that by loading diseased CAD-HDL with S1P.