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Am J Physiol Heart Circ Physiol (April 6, 2007). doi:10.1152/ajpheart.01352.2006
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Submitted on December 12, 2006
Accepted on April 3, 2007

Human recombinant Chromogranin A-derived Vasostatin-1 Mimics Preconditioning via an Adenosine/Nitric Oxide Signalling Mechanism

Sandra Cappello1, Tommaso Angelone2, Bruno Tota3, Pasquale Pagliaro4, Claudia Penna, Raffaella Rastaldo1, Angelo Corti5, Gianni Alberto Losano6*, and Maria Carmela Cerra2

1 Neuroscienze, University of Torino, Torino, Italy
2 Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Italy
3 CELL BIOLOGY, UNIVERSITY OF CALABRIA, ARCAVACATA DI RENDE, Italy
4 Scienze Cliniche e Biologiche, Universita di Torino, Orbassano, 10043, Italy; Scienze Cliniche e Biologiche, University of Torino, Orbassano, Italy
5 San Raffaele Sci Inst, Milano, Italy
6 Neuroscienze, Università di Torino, Torino, Italy

* To whom correspondence should be addressed. E-mail: raffaella.rastaldo{at}unito.it.

The acidic protein Chromogranin A (CGA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CGA N-terminal fragment STA-CGA1-78 (hrSTA-CGA1-78), containing vasostatin-1 (CGA1-76) domain, exerts negative inotropic effect and counteracts the {beta}-adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CGA1-78. We also hypothesized an involvement of adenosine A1 receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CGA1-78. Therefore we evaluate whether i) the cardio-inhibition mediated by hrSTA-CGA1-78 involves the Gi/0 proteins/NO-dependent signal transduction cascade; ii) hrSTA-CGA1-78 induces ischemic preconditioning-like protective effects on the myocardium; iii) inhibition of either NO synthase (NOS), adenosine A1 receptor or PKC affects hrSTA-CGA1-78 protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate pressure product and +(LVdP/dt)max elicited by hrSTA-CGA1-78 at 33nM is abolished by blocking Gi/0 proteins by PTx, by scavenging NO with hemoglobin, by blocking NOS activity with L-NMMA or L-NIO, soluble guanylate cyclase with ODQ, and PKG with KT5823. Data suggest the involvement of the Gi/0 proteins/NO-cGMP-PKG pathway in the hrSTA-CGA1-78-dependent cardio-inhibition. When given before 30 min of ischemia, hrSTA-CGA1-78 significantly reduced the size of the infarct from 64+/-4% to 32+/-3% of the left ventricular mass. This protective effect was abolished by either NOS inhibition or PKC blockade, and attenuated, but not suppressed, by the blockade of A1 receptors. These results suggest that hrSTA-CGA1-78 activity triggers two different pathways: one of these pathways is mediated by A1 receptors, the other is mediated by NO release. As with repeated-brief preconditioning ischemias, hrSTA-CGA1-78 may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.




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