Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro

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 P2Y 12 inhibitor. ticagrelorinduced 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 antiapoptotic 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. Acute myocardial infarction (AMI) is an adverse cardiac event leading to high risk of morbidity and mortality worldwide 1. Indeed, it has been demonstrated that a significant residual microvascular perfusion deficit remains after coronary revascularization 2 , which leads to cardiac cell death and progressive ventricular remodeling 3. Post-ischemic left ventricular (LV) remodeling is a complex scenario mainly characterized by progressive loss of cardiomyocytes due to apoptosis and alteration of intercellular cross talk following prolonged exposure to hypoxic microenvironment 3. In order to improve AMI care, adequate pharmacological approach to safely increase hypoxic tolerance of cardiomyocytes remains a critical need. Numerous experimental 4-8 and clinical 9-12 studies have shown that long-term antagonism of P2Y 12 , a G protein-coupled (GPCR) purinergic receptor, protects the myocardium against ischemic LV remodeling. Chronic administration of ticagrelor, a selective and reversible P2Y 12 receptor antagonist that does not require metabolic activation, is more cardioprotective than clopidogrel 13,14 , a prodrug that irreversibly inhibits P2Y 12. The non-thienopyridine P2Y 12 inhibitor such as ticagrelor enhances cardiomyocyte tolerance against ischemic microenvironment 4,7,8,15 beyond its clinical efficacy in preventing intracoronary platelet aggregation. Although previous studies suggested that cardioprotective pleiotropic effects of ticagrelor are dependent on the enhanced levels of adenosine 16 , this mechanistic relationship was recently questioned by others 17. In particular, 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. Although suc...

Roles and Clinical Applications of Exosomes in Cardiovascular Disease

“…Ticagrelor enhances the mitotic activity of CPCs and thus increases the number of the exosome level. Meanwhile, exosomes from CPC precondition with ticagrelor show improved antiapoptotic activity through the activation of the ERK1/2 pathway [60].…”

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development

“…Despite some trials on the use of somatic or cardiac MSCs with or without additional treatment of MSC-EVs are ongoing in China, Iran and US [135] , [157] , the International Society of Extracellular Vesicles (ISEV) and the International Society for Cell and Gene Therapy (ISCT) have very recently released a statement expressing specific concerns about EVs-based COVID-19 therapy [158] . Otherwise, ticagrelor, an established anti-platelet drug, drives the release of antiapoptotic exosomes from human cardiac-derived progenitors [159] , thereby suggesting an alternative approach to direct exosome transplantation in both vital organs beyond lowering the risk of thrombotic events.…”

Purinergic Regulation of Endothelial Barrier Function

“…P2Y 12 is well-studied in relation to platelet biology, and its antagonists are used clinically as anticoagulants in various pathological conditions. In human cardiac-derived mesenchymal cells, ticagrelor, a P2Y 12 receptor antagonist, induces the release of anti-apoptotic exosomes [ 147 ] that may also modulate the coronary microvascular endothelial barrier. Endothelial expression of both P2Y 12 [ 84 , 148 ] and P2Y 13 [ 104 ] has been documented.…”