Abstract
Cardioprotection against ischemia/reperfusion injury is still an unmet clinical need. The transient activation of Toll-like receptors (TLRs) has been implicated in cardioprotection, which may be achieved by treatment with blood-derived extracellular vesicles (EVs). However, since the isolation of EVs from blood takes considerable effort, the aim of our study was to establish a cellular model from which cardioprotective EVs can be isolated in a well-reproducible manner. EV release was induced in HEK293 cells with calcium ionophore A23187. EVs were characterized and cytoprotection was assessed in H9c2 and AC16 cell lines. Cardioprotection afforded by EVs and its mechanism were investigated after 16 h simulated ischemia and 2 h reperfusion. The induction of HEK293 cells by calcium ionophore resulted in the release of heterogenous populations of EVs. In H9c2 and AC16 cells, stressEVs induced the downstream signaling of TLR4 and heme oxygenase 1 (HO-1) expression in H9c2 cells. StressEVs decreased necrosis due to simulated ischemia/reperfusion injury in H9c2 and AC16 cells, which was independent of TLR4 induction, but not that of HO-1. Calcium ionophore-induced EVs exert cytoprotection by inducing HO-1 in a TLR4-independent manner.
Highlights
In ischemic heart disease, one of the leading causes of death—ischemia/reperfusion (I/R) injury—induces different cell death programs, e.g., necrotic and apoptotic pathways.Despite the intensive research activity in the field over the last 40 years, there is an unmet clinical need for efficacious cardioprotective treatments or interventions [2,3]
Dynamic light scattering (DLS) analysis revealed that particles that were released after HEK293 cells were treated with A23187 included large extracellular vesicles (EVs) (100–1000 nm in diameter) and a population with a diameter smaller than 100 nm
We provide evidence that the cytoprotection afforded by calcium ionophore-induced stressEVs is mediated by heme oxygenase 1 (HO-1), independently of their effect on Toll-like receptors (TLRs) signaling
Summary
Despite the intensive research activity in the field over the last 40 years, there is an unmet clinical need for efficacious cardioprotective treatments or interventions [2,3]. A number of mediators and mechanisms have been proposed to be involved in experimental cardioprotective mechanisms, for example, the activation of protein kinase C (PKC), nuclear factor kappa-B (NF-κB), or nitric oxide (NO) pathways (reviewed in [4,5]). Several mediators that can promote cytoprotective responses in the heart, such as heat shock proteins (HSPs) as representatives of damage-associated molecular patterns (DAMPs) [6], adenosine [7], or tumor necrosis factor alpha (TNFα), have been identified [8]. The development of novel cardioprotective treatments is of primary importance
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