Transcriptomic Landscape of Circulating Extracellular Vesicles in Heart Transplant Ischemia-Reperfusion

Ischemia-reperfusion injury (IRI) is an inevitable event during heart transplantation, which is known to exacerbate damage to the allograft. However, the precise mechanisms underlying IRI remain incompletely understood. Here, we profiled the whole transcriptome of plasma extracellular vesicles (EVs) by RNA sequencing from 41 heart transplant recipients immediately before and at 12 h after transplant reperfusion. We found that the expression of 1317 protein-coding genes in plasma EVs was changed at 12 h after reperfusion. Upregulated genes of plasma EVs were related to metabolism and immune activation, while downregulated genes were related to cell survival and extracellular matrix organization. In addition, we performed correlation analyses between EV transcriptome and intensity of graft IRI (i.e., cardiomyocyte injury), as well as EV transcriptome and primary graft dysfunction, as well as any biopsy-proven acute rejection after heart transplantation. We ultimately revealed that at 12 h after reperfusion, 4 plasma EV genes (ITPKA, DDIT4L, CD19, and CYP4A11) correlated with both cardiomyocyte injury and primary graft dysfunction, suggesting that EVs are sensitive indicators of reperfusion injury reflecting lipid metabolism-induced stress and imbalance in calcium homeostasis. In conclusion, we show that profiling plasma EV gene expression may enlighten the mechanisms of heart transplant IRI.

Automated summary

In this study, the transcriptome of plasma extracellular vesicles (EVs) was analyzed before and after transplant reperfusion in heart transplant recipients. The expression of 1317 protein-coding genes in plasma EVs was found to change after reperfusion. Upregulated genes in plasma EVs were related to metabolism and immune activation, while downregulated genes were related to cell survival and extracellular matrix organization. Furthermore, correlations were observed between EV transcriptome and graft ischemia-reperfusion injury, primary graft dysfunction, and acute rejection after heart transplantation. The study revealed that certain plasma EV genes were associated with cardiomyocyte injury and primary graft dysfunction, suggesting their potential as sensitive indicators of reperfusion injury.