Cardiac fibroblasts secrete exosome microRNA to suppress cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury

Abstract

Molecular mechanisms underlying myocardial ischemia/reperfusion (MI/R) injury and effective strategies to treat MI/R injury are both in shortage. Although pyroptosis of cardiomyocytes and the protective role of cardiac fibroblasts (CFs) have been well recognized as targets to reduce MI/R injury and sudden cardiac death (SCD), the connection has not yet been established. Here, we showed that CFs protected cardiomyocytes against MI/R-induced injury through suppression of pyroptosis. A novel molecular mechanism underpinning this effect was further identified. Under hypoxia/reoxygenation condition, CFs were found to secrete exosomes, which contain increased level of microRNA-133a (miR-133a). These exosomes then delivered miR-133a into cardiomyocytes to target ELAVL1 and repressed cardiomyocyte pyroptosis. Based on this finding, we successfully developed a new strategy that used exosomes derived from CFs with overexpressed miR-133a to enhance the therapeutic outcomes for the MI/R injury. Overall, our results provide a novel molecular basis for understanding and treating MI/R injury, and our study also provides novel insight for the postmortem diagnosis of MI/R injury induced SCD by using exosome biomarker in forensic.

1,3,8-Triazaspiro[4.5]decane Derivatives Inhibit Permeability Transition Pores through a FO-ATP Synthase c Subunit Glu119-Independent Mechanism That Prevents Oligomycin A-Related Side Effects

“…First, we evaluated the expression and proper localization of protein variants in human cardiac fibroblasts (HCF) cells, which allowed us to investigate PTP inhibition in a cardiac environment [ 36 , 37 ], but with the minimal contribution of endogenous Csub expression. Indeed, being fibroblasts a non-contractile cell type, thus requiring less ATP production compared with cardiomyocytes, they express lower levels of Csub ( Figure S1D ).…”

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

“…Furthermore, Dai et al demonstrated that M2 macrophage-derived exosomes carry microRNA-148A to inhibit the TXNIP and TLR4/NF-κB/NLRP3 signaling pathways, thereby alleviating myocardial I/R injury [ 73 ]. Liu et al illustrated that cardiac fibroblast-derived exosomes carry microRNA-133A to suppress cardiomyocyte pyroptosis in myocardial I/R injury, and Zhang et al indicated that hypoxic cardiac microvascular endothelial cell-derived exosomes carry microRNA-27b-3p to alleviate myocardial I/R Injury via the Foxo1/GSDMD signaling pathway [ 74 , 75 ]. Similar to their functions in cerebral I/R injury, the exosomes of mesenchymal stem cells can also mitigate myocardial I/R injury through inhibiting the canonical pathway of pyroptosis [ 76 , 77 ].…”

Research hotspots and development trends of microRNA in ischemia-reperfusion: network analysis of academic journals oriented by bibliometric and visualization

“…In the last 3 years, the relationship between miRNA in exosomes and IR has attracted increasing attention from researchers ( Figure 7 ). Their results have found that the miRNA of the exosomes of various cells, such as tubular epithelial cells ( 21 ), myocardial fibroblasts ( 22 ), bone marrow mesenchymal stem cells ( 23 ), human urine-derived stem cells ( 24 ), macrophages ( 25 ), cochlear spiral ganglion progenitor cells ( 26 ), and human umbilical cord mesenchymal stem cells (hUCMSCs) ( 27 ) are involved in the occurrence and development of IR.…”

“…tubular epithelial cells (21), myocardial fibroblasts (22), bone marrow mesenchymal stem cells (23), human urinederived stem cells (24), macrophages (25), cochlear spiral ganglion progenitor cells (26), and human umbilical cord mesenchymal stem cells (hUCMSCs) (27) are involved in the occurrence and development of IR. IR occurs in many organs.…”