Myocardial ischemia‐reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury

Abstract

Extracellular vesicles (EVs) curb important biological functions. We previously disclosed that ischemia‐reperfusion (IR) induces increased release of EVs (IR‐EVs) in the heart. However, the role of IR‐EVs in IR pathological process remains poorly understood. Here we found that adoptive transfer of IR‐EVs aggravated IR induced heart injury, and EV inhibition by GW4869 reduced the IR injury. Our in vivo and in vitro investigations substantiated that IR‐EVs facilitated M1‐like polarization of macrophages with increased expression of proinflammatory cytokines. Further, we disclosed the miRNA profile in cardiac EVs and confirmed the enrichment of miRNAs, such as miR‐155‐5p in IR‐EVs compared to EVs from the sham heart (S‐EVs). In particular, IR‐EVs transferred miR‐155‐5p to macrophages and enhanced the inflammatory response through activating JAK2/STAT1 pathway. Interestingly, IR‐EVs not only boosted the local inflammation in the heart, but even triggered systemic inflammation in distant organs. Taken together, we newly identify an IR‐EVs–miR‐155‐5p – M1 polarization axis in the heart post IR. The EVs derived from IR‐injured heart contribute to both local and systemic inflammation. Importantly, EV inhibition by GW4869 is supposed to be a promising therapeutic strategy for IR injury.

Hypoxia‐stimulated ATM activation regulates autophagy‐associated exosome release from cancer‐associated fibroblasts to promote cancer cell invasion

“…More importantly, exosomes released from these ATM‐inhibited hypoxic CAFs (Hyp‐CAF Ku‐Exo, Hyp‐CAF shATM‐Exo) decreased tumour cell invasive ability by 47.7%–50.8% compared with corresponding controls (Hyp‐CAF DMSO‐Exo, Hyp‐CAF shNC‐Exo, P < 0.01) (Figure S2D‐S2E , 12th vs. 10th, and 16th vs. 14th image/histogram on the right), suggesting that oxidized ATM in CAFs can promote tumour cell invasion mainly via exosome release. In addition, pharmacologically blocking exosome release from hypoxic CAFs (Figure S2F ) by GW4869, a non‐competitive N‐SMase inhibitor (Ge et al., 2021 ) with non‐detectable effect on the viability of CAFs (Figure S2G ), reduced the effect of Nor‐CAF‐CM on tumour cell invasion compared with Nor‐NF‐CM (Figure S2H‐S2I , 1st vs. 2nd or 3rd, 2nd or 3rd vs. 4th image/histogram on the left). Especially, the reduced effect of hypoxic CAFs‐derived CM caused by GW4869 treatment (Hyp‐CAF‐GW‐CM) on tumour cell invasion was more obvious compared with its control CM (Hyp‐CAF‐DMSO‐CM or Hyp‐CAF‐CM) (Figure S2H‐S2I , 5th or 6th vs. 7th image/histogram on the right).…”

Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia

“…Thus, we studied whether leukemic cell-derived sEVs play roles in affecting CD8+ T cell function. GW4869, an inhibitor of sEV secretion (Ge et al, 2021), decreased sEV secretion from leukemic cells (Figure S3C) and showed almost no effect on leukemic cell and CD8+ T cell viability (Figure S3D). Interestingly, blocking sEV secretion by leukemic cells with GW4869 rescued CD8+ T cell proliferation (Figures 2a and S4A), IL-2 and IFN-γ secretion (Figures 2b,c and S4B,C), CD25 expression (Figures 2d and S4D), and granzyme B production (Figures 2e and S4E).…”

Impact of the Main Cardiovascular Risk Factors on Plasma Extracellular Vesicles and Their Influence on the Heart’s Vulnerability to Ischemia-Reperfusion Injury

“…Increases cardiomyocyte apoptosis in vitro via the downregulation of HIF-1α, RNA-binding protein Quaking, and SIRT1 [153,154,198], enhances the inflammatory response through the activation of the JAK2/STAT1 pathway [155], increases ROS generation during IRI [199].…”