P2X7 Receptor Facilitates Cardiomyocyte Autophagy After Myocardial Infarction via Nox4/PERK/ATF4 Signaling Pathway.

Myocardial infarction (MI) represents a critical cardiovascular emergency, standing as a leading cause of global mortality. ATP, a typical damage-associated molecular pattern, is stored in cells at high concentrations. Upon cellular injury, hypoxia, or necrosis, substantial quantities of ATP efflux into the extracellular space, activating P2X7 receptors, thereby initiating multiple signaling cascades. In vivo studies demonstrated coordinated upregulation of P2X7 and autophagy-related proteins in the infarcted border zone. Transcriptome sequencing revealed Nox4 overexpression in the myocardial tissue post-infarction; furthermore, administration of the P2X7 receptor antagonist A740003 effectively reduced both autophagy-related protein levels and Nox4 expression. In vitro experiments indicated that hypoxia induced upregulation of Nox4, p-PERK/PERK, ATF4, Beclin-1, and ATG5 in cardiomyocytes, A740003 could inhibit the expression of these proteins, while overexpression of Nox4 counteracted this effect. Collectively, our findings indicated that the P2X7 receptor expression was elevated in the infarcted border zone following MI and implicated its role in excessive autophagy induced by hypoxia in cardiomyocytes-at least partially through the Nox4/PERK/ATF4 pathway, thereby exacerbating myocardial injury following MI.