title: E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role.
abstract: Ischemia/reperfusion (I/R) elicits renin release from cardiac mast cells (MC), thus activating a local renin-angiotensin system (RAS), culminating in ventricular fibrillation. We hypothesized that in I/R, neurogenic ATP could degranulate juxtaposed MC and that ecto-nucleoside triphosphate diphosphohydrolase 1/CD39 (CD39) on MC membrane could modulate ATP-induced renin release. We report that pharmacological inhibition of CD39 in a cultured human mastocytoma cell line (HMC-1) and murine bone marrow-derived MC with ARL67156 (100 µM) increased ATP-induced renin release (≥2-fold), whereas purinergic P2X7 receptors (P2X7R) blockade with A740003 (3 µM) prevented it. Likewise, CD39 RNA silencing in HMC-1 increased ATP-induced renin release (≥2-fold), whereas CD39 overexpression prevented it. Acetaldehyde, an I/R product (300 µM), elicited an 80% increase in ATP release from HMC-1, in turn, causing an autocrine 20% increase in renin release. This effect was inhibited or potentiated when CD39 was overexpressed or silenced, respectively. Moreover, P2X7R silencing prevented ATP- and acetaldehyde-induced renin release. I/R-induced RAS activation in ex vivo murine hearts, characterized by renin and norepinephrine overflow and ventricular fibrillation, was potentiated (∼2-fold) by CD39 inhibition, an effect prevented by P2X7R blockade. Our data indicate that by regulating ATP availability at the MC surface, CD39 modulates local renin release and thus, RAS activation, ultimately exerting a cardioprotective effect.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Aldi
authors.affiliation: Departments of Pharmacology and.
authors.forename: Alice
authors.initials: A
authors.lastname: Marino
authors.affiliation: Departments of Pharmacology and.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Departments of Pharmacology and.
authors.forename: Federico
authors.initials: F
authors.lastname: Corti
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; and Thrombosis Research Laboratory, Veterans Affairs New York Harbor Healthcare System, New York, New York, USA.
authors.forename: Ranjini
authors.initials: R
authors.lastname: Anand
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; and Thrombosis Research Laboratory, Veterans Affairs New York Harbor Healthcare System, New York, New York, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Olson
authors.affiliation: Pathology and Laboratory Medicine and Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; and Thrombosis Research Laboratory, Veterans Affairs New York Harbor Healthcare System, New York, New York, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marcus
authors.affiliation: Departments of Pharmacology and rlevi@med.cornell.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Levi
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000378:metabolism; D015550:Cell Degranulation; D002460:Cell Line; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology; D034741:RNA, Small Interfering / Q000235:genetics; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
chemical_list: C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D015703:Antigens, CD; D002316:Cardiotonic Agents; D034741:RNA, Small Interfering; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D012083:Renin; D001081:Apyrase; C067869:CD39 antigen
keywords: ATP; P2X7 purinergic receptors; arrhythmias; renin-angiotensin system; toxic aldehydes