Aldi Silvia, Marino Alice, Tomita Kengo, Corti Federico, Anand Ranjini, Olson Kim E, Marcus Aaron J, Levi Roberto
Departments of Pharmacology 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.
FASEB J. 2015 Jan;29(1):61-9. doi: 10.1096/fj.14-261867. Epub 2014 Oct 15.
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.
缺血/再灌注（I/R）引发心脏肥大细胞（MC）释放肾素，从而激活局部肾素-血管紧张素系统（RAS），最终导致心室颤动。我们推测，在I/R过程中，神经源性ATP可使相邻的MC脱颗粒，并且MC膜上的外核苷酸三磷酸二磷酸水解酶1/CD39（CD39）可调节ATP诱导的肾素释放。我们报告称，用ARL67156（100 μM）对培养的人肥大细胞瘤细胞系（HMC-1）和小鼠骨髓来源的MC进行CD39的药理学抑制，可增加ATP诱导的肾素释放（≥2倍），而用A740003（3 μM）阻断嘌呤能P2X7受体（P2X7R）则可防止这种情况。同样，HMC-1中CD39的RNA沉默增加了ATP诱导的肾素释放（≥2倍），而CD39的过表达则可防止这种情况。乙醛是一种I/R产物（300 μM），可使HMC-1的ATP释放增加80%，进而导致肾素释放自分泌增加20%。当CD39过表达或沉默时，这种效应分别受到抑制或增强。此外，P2X7R沉默可防止ATP和乙醛诱导的肾素释放。CD39抑制可增强离体小鼠心脏中I/R诱导的RAS激活，其特征为肾素和去甲肾上腺素溢出以及心室颤动（约2倍），P2X7R阻断可防止这种效应。我们的数据表明，通过调节MC表面的ATP可用性，CD39可调节局部肾素释放，从而调节RAS激活，最终发挥心脏保护作用。
