Title

 

Authors

 F. Corti^1,2, K.E. Olson³, A.J. Marcus³, M. Ziche², R. Levi^1
 
1Department of Pharmacology and Medicine, Weill Cornell Medical College, New York,USA
²Department of Molecular Biology, University of Siena, ITALY
³Division of Hematology-Oncology Medical Service of Veterans Administration New York Harbor Healthcare System, New York, USA
 

 

Abstract

A critical goal in the treatment of myocardial ischemia, congestive heart failure, and hypertension is to reduce excessive sympathetic activation so as to prevent the cardiotoxic effects of norepinephrine (NE) (Esler 2000; Grassi et al. 2009; Kubler et al. 1994). β-Blockers have been extensively used to alleviate ischemic arrhythmias, preserve left ventricular ejection fraction, and normalize blood pressure . Yet, β-blockers are not without disabling side effects (e.g., fatigue, muscle weakness, cold extremities, nightmares, and impotence) (Bohm et al. 2000)and have been shown to increase cardiac sympathetic innervation(Clarke et al. 2010). Thus, a prejunctional inhibition of abnormal NE release may offer advantages over blockade of NE effects at cardiac postsynaptic sites. One such means could entail a modulation of NE release by its co-transmitter ATP. Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves (Bonisch et al. 2006), whereas transmitter ATP is catabolized by E-NTPDase1/CD39, an ecto-ATPase (Zimmermann et al. 1999). Since ATP is known to modulate neurotransmitter release at pre-junctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in NGF-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine. We report that E-NTPDase1/CD39 deletion markedly increases depolarization-induced exocytosis of ATP and dopamine, and increases ATP-induced dopamine release. Moreover, overexpression of E-NTPDase1/CD39 resulted in enhanced removal of exogenous ATP, a marked decrease in exocytosis of ATP and dopamine, and a large decrease in ATP-induced dopamine release. Administration of a recombinant form of E-NTPDase1/CD39 reproduced the effects of E-NTPDase1/CD39 overexpression. Exposure of PC12 cells to simulated ischemia elicited a release of ATP and dopamine which was markedly increased in E-NTPDase1/CD39-silenced cells and decreased in E-NTPDase1/CD39-overexpressing cells. Therefore, transmitter ATP acts in an autocrine manner to promote its own release and that of dopamine, an action which is controlled by the level of E-NTPDase1/CD39 expression. Sympathetic hyperinnervation, enhanced adrenergic activity, and excessive catecholamine release are recognized causes of cardiac dysfunction and arrhythmias in myocardial ischemia, congestive heart failure, and hypertension. Thus, our findings identify a new protective role for neuronal E-NTPDase1/CD39, i.e., limitation of exaggerated catecholamine release in all of these conditions. In summary, since ATP availability greatly increases in myocardial ischemia, recombinant E-NTPDase1/CD39 (solCD39) therapeutically utilized may offer a novel approach to reduce cardiac dysfunctions due to excessive catecholamine release.
 
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