E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role.

Aldi, Silvia;Marino, Alice;Tomita, Kengo;Corti, Federico;Levi, Roberto;et.al.
(2015) FASEB journal : official publication of the Federation of American Societies for Experimental Biology — Vol. 29, n° 1, p. 61-69 (2015)

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Authors
  • Aldi, Silvia
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  • Marino, AliceUCLouvain
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  • Tomita, Kengo
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  • Corti, Federico
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  • Levi, Roberto
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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.
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Aldi, S., Marino, A., Tomita, K., Corti, F., Anand, R., Olson, K. E., Marcus, A. J., & Levi, R. (2015). E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 29(1), 61-69. https://doi.org/10.1096/fj.14-261867 (Original work published 2015)