MiR-21-5p-expressing bone marrow mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury by regulating the circRNA_0031672/miR-21-5p/programmed cell death protein 4 pathway

摘要

BACKGROUND For patients with coronary heart disease,reperfusion treatment strategies are often complicated by ischemia/reperfusion(I/R)injury(IRI),leading to serious organ damage and malfunction.The miR-21/programmed cell death protein 4(PDCD4)pathway is involved in the IRI of cardiomyocytes;however,the aberrant miR-21 expression remains unexplained.Therefore,this study aimed to explore whether circRNA_0031672 downregulates miR-21-5p expression during I/R and to dete-rmine whether miR-21-5p-expressing bone marrow mesenchymal stem cells(BMSCs)reduce myocardial IRI.METHODS CircRNA_0031672,miR-21-5p,and PDCD4 expressions were evaluated in the I/R rat model and hypoxia/re-oxy-genation(H/R)-treated H9C2 cells.Their interactions were subsequently investigated using luciferase reporter and RNA pull-down assays.Methyltransferase-like 3,a methyltransferase catalyzing N6-methyladenosine(m6A),was overexpressed in H9C2 cells to determine whether m6A modification influences miR-21-5p targeting PDCD4.BMSCs stably expressing miR-21 were co-cultured with H9C2 cells to investigate the protective effect of BMSCs on H9C2 cells upon H/R.RESULTS I/R downregulated miR-21-5p expression and upregulated circRNA_0031672 and PDCD4 expressions.CircRNA_0031672 knockdown increased miR-21-5p expression,but repressed PDCD4 expression,indicating that circRNA_0031672 com-petitively bound to miR-21-5p and prevented it from targeting PDCD4 mRNA.The m6A modification regulated PDCD4 expres-sion,but had no effect on miR-21-5p targeting PDCD4.The circRNA_0031672/miR-21-5p/PDCD4 axis regulated myocardial cells viability and apoptosis after H/R treatment;co-culture with miR-21-5p-expressing BMSCs restored miR-21-5p abundance in H9C2 cells and further reduced H9C2 cells apoptosis induced by H/R.CONCLUSIONS We identified a novel circRNA_0031672/miR-21-5p/PDCD4 signaling pathway that mediates the apoptosis of cardiomyocytes and successfully alleviates IRI in myocardial cells by co-culture with miR-21-5p-expressing BMSCs,offering novel insights into the IRI pathogenesis in cardiovascular diseases.