Exosomes derived from plasma of septic patients induce myocardial dysfunction

Background

Exosomes are small vesicles (50–100 nm) released from cells after activation. We have previously shown that exosomes derived from platelets of septic patients induce apoptosis of endothelial and vascular smooth muscle cells through a redox-dependent pathway. Since reactive oxygen species may be involved in myocardial dysfunction of sepsis, the aim of this study was to investigate a possible role of exosomes in sepsis-induced myocardial dysfunction.

Methods

Exosomes were separated by filtration and ultracentrifugation of plasma from 26 septic shock patients (SSP) and from 10 healthy volunteers. After separation, exosomes were infused at a 0.5-fold plasma concentration in Langendorff-perfused hearts from 22 New Zealand rabbits. In other experiments, 12 isolated rat papillary muscles were exposed to a 0.5-fold plasma concentration of exosomes from septic patients and healthy controls.

Results

Incubation of exosomes from SSP for 20 min induced a 17% and 30% reduction in positive and negative time–pressure derivatives, respectively (n = 7, P < 0.05). Incubation of exosomes from healthy volunteers for the same time induced a nonsignificant 9% and 19% decrease in positive and negative time–pressure derivatives, respectively (n = 5, P = NS). This effect was 60% and 83% inhibited by L-NMMA (10^-4 M). Exposure of rat papillary muscles to exosomes from SSP caused decrease in developed tension (3.22 ± 0.77 g/mm² pre vs 2.86 ± 0.80 g/mm² post, n = 8, P = 0.007) and in positive time-tension derivative (31.8 ± 9.32 g/mm²/s pre vs 28.06 ± 9.31 g/mm²/s post, n = 8, P = 0.01). Incubation with exosomes from healthy volunteers induced no significant difference in developed tension (3.08 ± 0.61 g/mm² pre vs 2.95 ± 0.72 g/mm² post, n = 4, P = NS) and in positive time-tension derivative (34.18 ± 6.03 g/mm²/s pre vs 34.45 ± 6.75 g/mm²/s post, n = 4, P = NS).

Conclusion

Infusion of exosomes from platelets of septic patients induces myocardial dysfunction in isolated rabbit hearts and in rat papillary muscle preparations. The attenuation of dysfunction after exposure to nitric oxide (NO) inhibitor L-NMMA indicates a possible role for NO in exosome-induced myocardial depression.