E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role
E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role
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DOI：
10.1096/fj.14-261867
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发表时间：
2015-01-01
期刊：
影响因子：
4.8
通讯作者：
Levi, Roberto
中科院分区：
文献类型：
--
作者：
Aldi, Silvia;Marino, Alice;Levi, Roberto
缺血/再灌注（I/R）引起心肌肥大细胞（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中，神经源性ATP可以使并置的MC脱粒，而MC膜上的外核苷三磷酸二磷酸水解酶1/CD39 （CD39）可以调节ATP诱导的肾素释放。我们报道了ARL67156 （100 μ M）在培养的人肥大细胞瘤细胞系（HMC-1）和小鼠骨髓源性MC中对CD39的药理学抑制增加了atp诱导的肾素释放（>= 2倍），而A740003 （3 mM）阻断嘌呤能P2X(7)受体（P2X(7)R）则阻止了它的释放。同样，HMC-1中CD39 RNA沉默增加了atp诱导的肾素释放（>= 2倍），而CD39过表达阻止了它的释放。乙醛，一种I/R产物（300 mM），引起HMC-1中ATP释放增加80%，进而引起肾素释放自分泌增加20%。当CD39过表达或沉默时，这种作用分别被抑制或增强。此外，P2X(7)R沉默可阻止ATP和乙醛诱导的肾素释放。在离体小鼠心脏中，I/R诱导的RAS激活，以肾素和去甲肾上腺素溢出和心室颤动为特征，通过CD39抑制而增强（类似于2倍），P2X(7)R阻断阻止了这一作用。我们的数据表明，通过调节MC表面ATP的可用性，CD39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。
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 mu M) increased ATP-induced renin release (>= 2-fold), whereas purinergic P2X(7) receptors (P2X(7)R) blockade with A740003 (3 mM) 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 mM), 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, P2X(7)R 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 (similar to 2-fold) by CD39 inhibition, an effect prevented by P2X(7)R 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.