The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH2-terminal fragment STA-CgA1-78 (hrSTA-CgA1-78), containing vasostatin-1 (CgA1-76) domain, exerts a negative inotropic effect and counteracts the β-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 evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA1-78 involves the G i/o proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA1-78 induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of 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 maximal values of the first derivative of LVP elicited by hrSTA-CgA1-78 at 33 nM is abolished by blocking Gi/o proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with NG-monomethyl-L-arginine or N5-(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 Gi/o proteins/NO-cGMP-PKG pathway in the hrSTA-CgA1-78-dependent cardioinhibition. 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 was attenuated, but not suppressed, by the blockade of A 1 receptors. These results suggest that hrSTA-CgA1-78 activity triggers two different pathways: one of these pathways is mediated by A1 receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA1-78 may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Publication status||Published - Jul 2007|
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