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.

Nox4; P2X7 receptor; autophagy; myocardial infarction; transcriptome sequencing.