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

• Published in: Cell biochemistry and function Vol. 43; no. 5; pp. e70078 - n/a
• Main Authors: Zhang, Shuhong, Bi, Yingying, Xiang, Kaili, Tang, Yanhong
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01.05.2025
• Subjects: Autophagy; Cardiomyocytes; Damage patterns; Efflux; Heart attacks; Hypoxia; In vivo methods and tests; Myocardial infarction; Necrosis; Nox4; NOX4 protein; P2X7 receptor; Proteins; Receptors; Signal transduction; transcriptome sequencing; Transcriptomes; Up-regulation
• ISSN: 0263-6484; 1099-0844; 1099-0844
• DOI: 10.1002/cbf.70078

ABSTRACT 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. Summary Myocardial infarction (MI) remains a global health crisis with limited therapeutic strategies targeting pathological autophagy. This study identifies the P2X7/Nox4/PERK/ATF4 axis as a critical driver of hypoxia‐induced cardiomyocyte autophagic overload post‐MI. Mechanistically, accumulation of extracellular ATP activates P2X7 receptors, upregulating Nox4‐dependent ROS production and ultimately amplifying autophagy and myocardial damage. Crucially, pharmacological inhibition of P2X7 normalizes this maladaptive cascade, while Nox4 overexpression reverses cardioprotective effects, establishing causal relationships. These findings not only elucidate a previously unrecognized ATP‐P2X7‐Nox4 crosstalk governing post‐infarction autophagy but also position P2X7 antagonism as a promising strategy to mitigate ischemia‐related myocardial remodeling, offering dual therapeutic advantages in controlling oxidative stress and preserving cardiomyocyte homeostasis. Summary Myocardial infarction (MI) remains a global health crisis with limited therapeutic strategies targeting pathological autophagy. This study identifies the P2X7/Nox4/PERK/ATF4 axis as a critical driver of hypoxia‐induced cardiomyocyte autophagic overload post‐MI. Mechanistically, accumulation of extracellular ATP activates P2X7 receptors, upregulating Nox4‐dependent ROS production and ultimately amplifying autophagy and myocardial damage. Crucially, pharmacological inhibition of P2X7 normalizes this maladaptive cascade, while Nox4 overexpression reverses cardioprotective effects, establishing causal relationships. These findings not only elucidate a previously unrecognized ATP‐P2X7‐Nox4 crosstalk governing post‐infarction autophagy but also position P2X7 antagonism as a promising strategy to mitigate ischemia‐related myocardial remodeling, offering dual therapeutic advantages in controlling oxidative stress and preserving cardiomyocyte homeostasis.