Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Cell Signaling

Background:

• High-density lipoproteins (HDLs) offer cardioprotection through mechanisms beyond reverse cholesterol transport.
• HDL-mediated signaling pathways in cardiomyocytes are activated by HDL receptor binding, but downstream targets remain unclear.
• Sphingosine-1-phosphate (S1P), an HDL constituent, is investigated for its role in limiting cardiac cell death during ischemia-reperfusion (I/R).

Purpose of the Study:

• To investigate the molecular pathways by which HDL-derived S1P limits cardiomyocyte death induced by cardiac I/R injury.
• To determine the role of the apolipoprotein M (ApoM)/S1P axis in protecting the heart against I/R damage.

Main Methods:

• Utilized apolipoprotein M (ApoM) transgenic mice with elevated plasma S1P and wild-type mice subjected to in vivo I/R.
• Conducted in vitro and ex vivo studies on isolated cardiomyocytes and perfused hearts to assess S1P effects and signaling.
• Investigated the phosphorylation of Connexin43 (Cx43) at Serine368 (S368) mediated by S1P receptors (S1P2, S1P3) and its functional significance.

Main Results:

• ApoM transgenic mice exhibited reduced infarct size, neutrophil infiltration, and serum Troponin I levels post-I/R compared to wild-type mice.
• Short-term S1P treatment at reperfusion onset significantly reduced I/R injury in isolated hearts.
• S1P treatment induced Cx43 phosphorylation at S368 via S1P2/S1P3 receptors, which was crucial for the observed cardioprotection, as demonstrated by studies using Cx43 mutant mice.

Conclusions:

• The ApoM/S1P axis plays a critical role in limiting cardiac I/R injury.
• S1P-mediated phosphorylation of Cx43 on S368 is a key molecular mechanism underlying S1P-induced cardioprotection.
• Modulating the ApoM/S1P pathway represents a potential therapeutic strategy for treating cardiac I/R injury.