A mechanistic axis of shear stress, reactive oxygen species, and microRNAs underlying endothelial dysfunction in myocardial infarction.

BACKGROUND: Obstructive myocardial infarction (MI) is well studied, whereas non-obstructive MI phenotypes, including myocardial infarction with non-obstructive coronary arteries (MINOCA), remain underexplored. Endothelial dysfunction (ED) is increasingly implicated in the pathophysiology of myocardial infarction. Vascular shear stress can modulate intracellular reactive oxygen species (ROS), which are the molecular mediators of its effects on the cell. Physiological shear stress maintains endothelial health, whereas ‘certain ranges’ disrupt ROS homeostasis and may cause ED. Further, some microRNAs (miRNAs) that regulate cellular processes are shear-responsive. Here, we integrated shear stress, ROS, and miRNA regulation into a proposed mechanistic axis driving ED in MI. METHODS AND RESULTS: An integrated bioinformatic and experimental study was used to identify shear stress-responsive, ROS-associated miRNAs with regulatory roles in MI. Publicly available MI patient datasets were analysed to identify differentially expressed shear stress-responsive miRNAs and their targets. Experimental validation was performed using EA. hy926 endothelial cells exposed to flow with shear rates 0.942, 1.57, 3.77, 9.42, and 14.13 s-¹. Analysis identified six differentially expressed miRNAs, shear stress-responsive and ROS-associated, targeting 31 upregulated mRNAs. Among them, hsa-miR-19a-3p and hsa-miR-155-5p were consistently downregulated. Network analysis revealed THBS1, SOCS1, SOCS3, and CEBPB as key miRNA targets linked to MI. Experimental validation confirmed shear-associated ROS generation, differential expression of hsa-miR-19a-3p and hsa-miR-155-5p, and their targets at the mRNA level. CONCLUSION: Together, these findings suggest a shear stress-ROS-miRNA regulatory axis in endothelial cells that is consistent with MI-associated transcriptional signatures and provides a mechanistic basis for future investigation of endothelial regulation in myocardial infarction.