MiR-17-5p-mediated endoplasmic reticulum stress promotes acute myocardial ischemia injury through targeting Tsg101.

Cardiovascular diseases are the leading cause of death globally, among which acute myocardial infarction (AMI) frequently occurs in the heart and proceeds from myocardium ischemia and endoplasmic reticulum (ER) stress-induced cell death. Numerous studies on miRNAs indicated their potential as diagnostic biomarkers and treatment targets for heart diseases. Our study investigated the role of miR-17-5p and its regulatory mechanisms during AMI. Echocardiography, MTT, flow cytometry assay, evaluation of caspase-3 and lactate dehydrogenase (LDH) activity were conducted to assess cell viability, apoptosis in an MI/R mice model, and an H2O2-induced H9c2 hypoxia cell model, respectively. The expression levels of ER stress response-related biomarkers were detected using qRT-PCR, IHC, and western blotting assays. The binding site of miR-17-5p on Tsg101 mRNA was determined by bioinformatic prediction and luciferase reporter assay. The expression levels of miR-17-5p were notably elevated in MI/R mice and hypoxia cell models, accompanied by enhanced cell apoptosis. Inhibition of miR-17-5p led to decreased apoptosis related to ER stress response in the hypoxia model, which could be counteracted by knockdown of Tsg101 (tumor susceptibility gene 101). Transfection with miR-17-5p mimics downregulated the expression of Tsg101 in H9c2 cells. Luciferase assay demonstrated the binding between miR-17-5p and Tsg101. Moreover, 4-PBA, the inhibitor of the ER stress response, abolished shTsg101 elevated apoptosis in hypoxic H9c2 cells. Our findings investigated the pro-apoptotic role of miR-17-5p during MI/R, disclosed the specific mechanism of miR-17-5p/Tsg101 regulatory axis in ER stress-induced myocardium injury and cardiomyocytes apoptosis, and presented a promising diagnostic biomarker and potential target for therapy of AMI.