PDCD4/PPARα axis regulates oxidative stress-mediated microvascular endothelial injury in myocardial ischemia-reperfusion.

Abstract

Cardiac microvascular endothelial cell (CMEC) injury is a primary driver of microvascular obstruction and the no-reflow phenomenon during myocardial ischemia/reperfusion (I/R). While Programmed Cell Death 4 (PDCD4) is known to exacerbate cardiovascular diseases, its precise role and regulatory mechanisms in CMEC barrier dysfunction and inflammatory adhesion during I/R remain unclear. In this study, we demonstrate that PDCD4 deletion significantly mitigates I/R-induced cardiac dysfunction, reduces infarct size, and preserves microvascular ultrastructure in mice. In vitro experiments using a hypoxia/reoxygenation (H/R) model revealed that PDCD4 knockdown preserves CMEC viability, suppresses apoptosis, and maintains endothelial barrier integrity by restoring tight junction proteins (ZO-1, Claudin-1, and Occludin). Furthermore, PDCD4 inhibition significantly reduced pathological permeability and attenuated the adhesion of neutrophils and macrophages by downregulating ICAM-1. Mechanistically, PDCD4 directly interacts with Peroxisome Proliferator-Activated Receptor alpha (PPARα) at the protein level and restricts its protective antioxidant function. Co-immunoprecipitation and immunofluorescence supported this interaction. Silencing PDCD4 restored PPARα-dependent antioxidant responses, leading to a marked reduction in oxidative stress (decreased ROS and MDA, increased SOD). Crucially, double-knockdown rescue experiments confirmed that the protective effects of PDCD4 depletion against H/R-induced apoptosis, barrier disruption, and inflammatory adhesion were largely abolished upon concurrent PPARα silencing. These findings establish that PDCD4 exacerbates I/R-induced CMEC injury by binding to and inhibiting PPARα-mediated antioxidant homeostasis. Targeting the PDCD4-PPARα interaction axis presents a promising therapeutic strategy to prevent microvascular dysfunction and improve outcomes following acute myocardial infarction.