Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Ryzhov, Sergey; Sung, Bong Hwan; Zhang, Qinkun; Weaver, Alissa M.; Gumina, Richard J.; Biaggioni, Italo; Feoktistov, Igor

doi:10.1007/s11302-014-9410-y

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…In 1986, Dubey et al (112) first reported that ADO inhibits cardiac fibroblast collagen production via stimulation of A 2 B receptors. Later work further indicated that maneuvers that increase intracellular cAMP diminish collagen production by cardiac fibroblasts (113, 114). This observation led to the demonstration of the homeostatic role of ATP hydrolysis, by the action of ENTPD (CD39) in diminishing collagen production by increasing extracellular ADO levels, which act at A 2 B receptors to raise cAMP and diminish fibroblast production of collagen (115).…”

Section: Modulation Of Peritoneal and Cardiac Fibrosis By Adomentioning

confidence: 99%

Purinergic signaling in scarring

et al. 2015

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Adenosine (ADO) and nucleotides such as ATP, ADP, and uridine 5'-triphosphate (UTP), among others, may serve as extracellular signaling molecules. These mediators activate specific cell-surface receptors-namely, purinergic 1 and 2 (P1 and P2)-to modulate crucial pathophysiological responses. Regulation of this process is maintained by nucleoside and nucleotide transporters, as well as the ectonucleotidases ectonucleoside triphosphate diphosphohydrolase [ENTPD; cluster of differentiation (CD)39] and ecto-5'-nucleotidase (5'-NT; CD73), among others. Cells involved in tissue repair, healing, and scarring respond to both ADO and ATP. Our recent investigations have shown that modulation of purinergic signaling regulates matrix deposition during tissue repair and fibrosis in several organs. Cells release adenine nucleotides into the extracellular space, where these mediators are converted by CD39 and CD73 into ADO, which is anti-inflammatory in the short term but may also promote dermal, heart, liver, and lung fibrosis with repetitive signaling under defined circumstances. Extracellular ATP stimulates cardiac fibroblast proliferation, lung inflammation, and fibrosis. P2Y2 (UTP/ATP) and P2Y6 [ADP/UTP/uridine 5'-diphosphate (UDP)] have been shown to have profibrotic effects, as well. Modulation of purinergic signaling represents a novel approach to preventing or diminishing fibrosis. We provide an overview of the current understanding of purinergic signaling in scarring and discuss its potential to prevent or decrease fibrosis.-Ferrari, D., Gambari, R., Idzko, M., Müller, T., Albanesi, C., Pastore, S., La Manna, G., Robson, S. C., Cronstein, B. Purinergic signaling in scarring

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Section: Modulation Of Peritoneal and Cardiac Fibrosis By Adomentioning

confidence: 99%

Purinergic signaling in scarring

et al. 2015

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“…, a low-affinity adenosine receptor even expressed by cardiac mesenchymal stem-like cells 46 that arrest cell cycle 46 . In order to highlight the dose-dependent role of adenosine as mediator of ticagrelor effects, we have also performed further experiments by adding exogenous adenosine.…”

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confidence: 99%

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

Casieri

Matteucci

Pasanisi

et al. 2020

Sci Rep

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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...

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“…In fact, it modulated osteoblast differentiation [227]. Moreover, these receptors also regulate myocardial repair and remodeling by delaying the deactivation of myofibroblasts [228].…”

Section: Selective Full Agonist Antagonist/partial Agonist Allostericmentioning

confidence: 99%

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

Effendi

Nagano

Kobayashi

et al. 2020

Cells

122

103

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Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A1AR, A2AAR, A2BAR, and A3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A1AR and A2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A2BAR and A3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.

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Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Cited by 19 publications

References 41 publications

Purinergic signaling in scarring

Purinergic signaling in scarring

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

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

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