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

<jats:p> The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH<jats:sub>2</jats:sub>-terminal fragment STA-CgA<jats:sub>1-78</jats:sub> (hrSTA-CgA<jats:sub>1-78</jats:sub>), containing vasostatin-1 (CgA<jats:sub>1-76</jats:sub>) 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-CgA<jats:sub>1-78</jats:sub>. We also hypothesized an involvement of adenosine A<jats:sub>1</jats:sub> receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA<jats:sub>1-78</jats:sub>. Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA<jats:sub>1-78</jats:sub> involves the G<jats:sub>i/o</jats:sub> proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA<jats:sub>1-78</jats:sub> induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO synthase (NOS), adenosine A<jats:sub>1</jats:sub> receptor, or PKC affects hrSTA-CgA<jats:sub>1-78</jats:sub> 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<jats:sub>1-78</jats:sub> at 33 nM is abolished by blocking G<jats:sub>i/o</jats:sub> proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with N<jats:sup>G</jats:sup>-monomethyl-l-arginine or N<jats:sup>5</jats:sup>-(iminoethyl)-l-ornithine, soluble guanylate cyclase with 1 H-[1,2,4]oxadiazole-[4,4-a]quinoxalin-1-one, and protein kinase (PKG) with KT5823. Data suggest the involvement of the G<jats:sub>i/o</jats:sub> proteins/NO-cGMP-PKG pathway in the hrSTA-CgA<jats:sub>1-78</jats:sub>-dependent cardioinhibition. When given before 30 min of ischemia, hrSTA-CgA<jats:sub>1-78</jats:sub> 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<jats:sub>1</jats:sub> receptors. These results suggest that hrSTA-CgA<jats:sub>1-78</jats:sub> activity triggers two different pathways: one of these pathways is mediated by A<jats:sub>1</jats:sub> receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA<jats:sub>1-78</jats:sub> may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC. </jats:p>