01352.2006.—The acidic protein chromograninA (CgA) is the precursor of several regulatory peptides generated byspecific proteolytic processes. Human recombinant CgA NH2-terminalfragment STA-CgA1-78 (hrSTA-CgA1-78), containing vasostatin-1(CgA1-76) domain, exerts a negative inotropic effect and counteractsthe -adrenergic positive inotropic effect on the rat heart. We hypothesizedan involvement of nitric oxide (NO)-dependent pathway inboth cardiodepression and cardioprotection by hrSTA-CgA1-78. Wealso hypothesized an involvement of adenosine A1 receptor andprotein kinase C (PKC) in cardioprotection by hrSTA-CgA1-78.Therefore, we evaluated whether 1) the cardioinhibition mediated byhrSTA-CgA1-78 involves the Gi/o proteins/NO-dependent signal transductioncascade, 2) hrSTA-CgA1-78 induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NOsynthase (NOS), adenosine A1 receptor, or PKC affects hrSTACgA1-78 protection. Using the isolated rat heart, we found that thereduction of left ventricular pressure (LVP), rate-pressure product,and maximal values of the first derivative of LVP elicited by hrSTACgA1-78 at 33 nM is abolished by blocking Gi/o proteins with pertussistoxin, scavenging NO with hemoglobin, and blocking NOS activitywith NG-monomethyl-L-arginine or N5-(iminoethyl)-L-ornithine, solubleguanylate cyclase with 1H-[1,2,4]oxadiazole-[4,4-a]quinoxalin-1-one, and protein kinase (PKG) with KT5823. Data suggest theinvolvement of the Gi/o proteins/NO-cGMP-PKG pathway in thehrSTA-CgA1-78-dependent cardioinhibition. When given before 30min of ischemia, hrSTA-CgA1-78 significantly reduced the size of theinfarct from 64 4 to 32 3% of the left ventricular mass. Thisprotective effect was abolished by either NOS inhibition or PKCblockade and was attenuated, but not suppressed, by the blockade ofA1 receptors. These results suggest that hrSTA-CgA1-78 activitytriggers two different pathways: one of these pathways is mediated byA1 receptors, and the other is mediated by NO release. As withrepeated brief preconditioning ischemia, hrSTA-CgA1-78 may beconsidered a stimulus strong enough to trigger both pathways, whichmay converge on PKC.
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|Titolo:||Human recombinant Chromogranin A-derived Vasostatin-1 Mimics Preconditioning via an Adenosine/Nitric Oxide Signalling Mechanism|
|Data di pubblicazione:||2007|
|Appare nelle tipologie:||1.1 Articolo in rivista|