Abstract
Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y12 inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering anti-apoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hCPCs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hCPCs.
Highlights
Numerous experimental[4,5,6,7,8] and clinical[9,10,11,12] studies have shown that long-term antagonism of P2Y12, a G protein-coupled (GPCR) purinergic receptor, protects the myocardium against ischemic LV remodeling
Since P2Y12 receptors are generally expressed in progenitor cells[27], it is conceivable that long-term antagonism of P2Y12 receptor of human Cardiac-derived progenitor cells (CPCs) by ticagrelor may promote the release of exosomes protecting cardiomyocytes against hypoxia-induced apoptosis
We have demonstrated that long-term treatment of viable human cardiac-derived mesenchymal progenitor cells with 1 μmol ticagrelor increases the release of TGS101 + and CD63 + exosomes delivering anti-apoptotic heat shock protein 70 (HSP70) as consequence of increased number of viable hCPCs
Summary
Numerous experimental[4,5,6,7,8] and clinical[9,10,11,12] studies have shown that long-term antagonism of P2Y12, a G protein-coupled (GPCR) purinergic receptor, protects the myocardium against ischemic LV remodeling. Recent study demonstrated that higher dose of ticagrelor (10 μM/L), which potentiates extracellular adenosine concentration compared to lower dose[18], failed to protect ischemic reperfused rodent heart[19] Such a high dose of ticagrelor has not yet been tested in patients, we cannot exclude that chronic P2Y12 antagonism by lower dose of ticagrelor may lead to cardioprotective milieu in the myocardium through hitherto unexpected pleiotropic effects. Cardiac-derived progenitor cells (CPCs), non-myocyte cells expressing mesenchymal/stromal cell surface markers even termed cardiac-derived mesenchymal progenitor cells, are involved in myocardial homeostasis after injury[20] These cells are able to release exosomes, smallest membrane-surrounded extracellular nanovesicles, which hamper cardiomyocyte apoptosis due to serum-nutrient starvation in a dose-dependent manner and attenuate LV remodeling in infarcted rodent heart[21,22,23]. We have used a well-characterized in vitro model of ischemic/ hypoxic cardiomyocyte death based on murine HL1 cardiomyocytes chronically exposed to severe hypoxia[28]
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