Background: Sphingosine-1-Phosphate receptor (S1PR) modulators are widely used in the treatment of multiple sclerosis due to the immunomodulatory effects. However, given the ubiquitous expression of S1PRs, S1PR modulators also impact the cardiovascular system. Previous studies have demonstrated that pretreatment with S1PR modulator can enhance cardiac recovery after acute myocardial infarction. Despite this, S1PR modulators are not routinely used as preventive therapy in clinical practice for myocardial infarction. Therefore, this study aimed to determine the optimal timing for initiating S1PR modulators treatment after revascularization to preserve their cardioprotective functions.
Methods: Myocardial infarction (MI) was induced in male wildtype mice via open-chest ischemia/reperfusion (I/R) surgery. Cardiac function was detected by echocardiography one day prior to and 21 days after I/R surgery. Treatment with various S1PR modulators, including fingolimod (FTY), siponimod (SPM), ozanimod (OZA) and ponesimod (PON), was initiated at different timepoints: one-hour, 24 hours and 48 hours post-MI. The scar size was evaluated on day 21 post-reperfusion using picrosirius red staining.
Results: Compared to the control group, S1PR modulator treatment initiated within one-hour post-reperfusion showed increased ejection fraction (EF) and reduced scar size in heart tissue after 21 days of reperfusion (EF: Ctrl 32.40±4.27% [n=8], FTY 39.81±3.80% [n=8], p=0.0104; OZA 39.30±5.91% [n=8], p=0.0184; PON 41.31±2.91% [n=8], p=0.0018. Scar size: Ctrl 24.84±3.81% [n=8], FTY 17.58±6.04% [n=8], p=0.0281; OZA 17.37±4.25% [n=8], p=0.0231; PON 15.56±5.05% [n=8], p=0.0036). Similar cardioprotective effects were observed when S1PR modulator treatment initiated 24 hours post-reperfusion (EF: Ctrl 32.40±4.27% [n=8], FTY 40.93±2.76% [n=8], p=0.0003; OZA 42.03±3.90% [n=8], p<0.0001; PON 43.05±3.16% [n=8], p<0.0001. Scar size: Ctrl 24.84±3.81% [n=8], FTY 12.54±3.41% [n=8], p<0.0001; OZA 18.88±4.23% [n=8], p=0.0408; PON 15.80±5.22% [n=8], p=0.0011). However, these beneficial effects were abolished when S1PR modulator treatment was delayed until 48 hours post-reperfusion (EF: Ctrl 32.40±4.27% [n=8], FTY 32.02±3.14% [n=8], p=0.9979; OZA 28.08±3.53% [n=8], p=0.1875; PON 31.39±5.39% [n=8], p=0.9627. Scar size: Ctrl 24.84±3.81% [n=8], FTY 18.42±4.53% [n=8], p=0.1217; OZA 22.15±7.35% [n=8], p=0.7712; PON 22.81±5.94% [n=8], p=0.8857).
Summary: Our study demonstrated that initiating therapy with S1PR modulators within 24 hours post myocardial infarction is the optimal time for improving cardiac recovery. Although S1PR modulators target different S1PR subtypes, they all exhibit the same cardioprotective effects. Future studies are needed to elucidate the underlying mechanisms of these cardioprotective effects.
