title: 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.
authors.affiliation: Dipartimento di Neuroscienze, Sezione di Fisiologia, Università di Torino, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cappello
authors.forename: Tommaso
authors.initials: T
authors.lastname: Angelone
authors.forename: Bruno
authors.initials: B
authors.lastname: Tota
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rastaldo
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Gianni
authors.initials: G
authors.lastname: Losano
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Cerra
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D053379:Chromogranin A / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D053379:Chromogranin A; D010446:Peptide Fragments; D011994:Recombinant Proteins; C505867:chromogranin A (1-78); C064110:vasostatin I; D009569:Nitric Oxide; D000241:Adenosine