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Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism.

Abstract
The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH(2)-terminal fragment STA-CgA(1-78) (hrSTA-CgA(1-78)), containing vasostatin-1 (CgA(1-76)) domain, exerts a 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-CgA(1-78). We also hypothesized an involvement of adenosine A(1) receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA(1-78). Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA(1-78) involves the G(i/o) proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA(1-78) induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO synthase (NOS), adenosine A(1) receptor, or PKC affects hrSTA-CgA(1-78) protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate-pressure product, and maximal values of the first derivative of LVP elicited by hrSTA-CgA(1-78) at 33 nM is abolished by blocking G(i/o) proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with N(G)-monomethyl-l-arginine or N(5)-(iminoethyl)-l-ornithine, soluble guanylate cyclase with 1H-[1,2,4]oxadiazole-[4,4-a]quinoxalin-1-one, and protein kinase (PKG) with KT5823. Data suggest the involvement of the G(i/o) proteins/NO-cGMP-PKG pathway in the hrSTA-CgA(1-78)-dependent cardioinhibition. When given before 30 min of ischemia, hrSTA-CgA(1-78) 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 was attenuated, but not suppressed, by the blockade of A(1) receptors. These results suggest that hrSTA-CgA(1-78) activity triggers two different pathways: one of these pathways is mediated by A(1) receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA(1-78) may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.
AuthorsSandra Cappello, Tommaso Angelone, Bruno Tota, Pasquale Pagliaro, Claudia Penna, Raffaella Rastaldo, Angelo Corti, Gianni Losano, Maria Carmela Cerra
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 293 Issue 1 Pg. H719-27 (Jul 2007) ISSN: 0363-6135 [Print] United States
PMID17416598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chromogranin A
  • Peptide Fragments
  • Recombinant Proteins
  • chromogranin A (1-78)
  • vasostatin I
  • Nitric Oxide
  • Adenosine
Topics
  • Adenosine (metabolism)
  • Animals
  • Chromogranin A (administration & dosage, genetics)
  • Humans
  • In Vitro Techniques
  • Ischemic Preconditioning (methods)
  • Male
  • Myocardial Reperfusion Injury (physiopathology, prevention & control)
  • Nitric Oxide (metabolism)
  • Peptide Fragments (administration & dosage, genetics)
  • Rats
  • Rats, Wistar
  • Recombinant Proteins (administration & dosage)
  • Signal Transduction (drug effects)

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