ATP-induced cardioprotection against myocardial ischemia/reperfusion injury is mediated through the RISK pathway

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Myocardial infarction (MI) remains a leading cause of mortality worldwide.
• Identifying effective therapeutic strategies to limit infarct size and preserve cardiac function is crucial.
• Adenosine-5 riphosphate (ATP) has shown potential in cardioprotection, but its precise mechanisms post-ischemia require further elucidation.

Purpose of the Study:

• To investigate the acute effects of post-infarct adenosine-5 riphosphate (ATP) administration on myocardial infarction (MI) size.
• To elucidate the molecular mechanisms underlying ATP-mediated cardioprotection.

Main Methods:

• A rabbit model of myocardial ischemia-reperfusion was established.
• Animals received intravenous ATP or saline immediately after reperfusion.
• Pharmacological inhibitors (wortmannin, PD-98059, 5-HD) were used to probe molecular pathways.
• Infarct size, cardiomyocyte apoptosis (TUNEL assay), and protein expression (Western blot for Akt/p-Akt, ERK/p-ERK) were assessed.

Main Results:

• Post-ischemic ATP administration significantly reduced infarct size compared to controls (p<0.05).
• The infarct-limiting effect of ATP was abolished by wortmannin, PD-98059, and 5-HD.
• ATP significantly decreased cardiomyocyte apoptosis, an effect abrogated by the inhibitors.
• Western blot analysis showed increased myocardial expression of phosphorylated Akt (p-Akt) and phosphorylated ERK (p-ERK) in the ATP group.

Conclusions:

• Post-ischemic ATP administration confers cardioprotection by reducing myocardial infarct size and cardiomyocyte apoptosis.
• The protective effects of ATP are mediated via activation of the reperfusion injury salvage kinase (RISK) pathway.
• Opening of mitochondrial ATP-dependent potassium channels is also implicated in ATP-induced cardioprotection.