Direct cardiac role of full-length human Chromogranin A: stimulus-induced processing and myocardial and coronary effects

The cardiovascular role of Chromogranin A (CgA) and its proteolytic fragments is well documented. Its plasma levels correlate with severe cardiovascular diseases (Ceconi et al., 2002). Moreover, the CgA-derived peptides Vasostatin-1 and Catestatin elicit cardiosuppression via anti-adrenergic-Nitric Oxide-cGMP mediated mechanism (Angelone et al., 2008). Here we evaluated whether and to which extent: i) intracardiac CgA processing is affected by physical (heart perfusion) and/or chemical stimuli (Isoproterenol: Iso, and Endothelin-1: ET-1); ii) the full-length CgA exerts direct cardiac activity. By using both Langendorff and Western Blotting techniques we found that, the perfusion itself, as well as Iso and ET-1 stimulation, induce cardiac CgA processing in low molecular weight fragments. We also found that CgA (1 and 4 nM) dilated coronaries and induced negative inotropism and lusitropism which disappeared at higher concentrations (10 and 16 nM). The increased eNOS phosphorylation in CgA treated hearts indicated the involvement of the NO-cGMP-PKG cascade. We suggest that: i) the heart generates CgA fragments in response to hemodynamic and excitatory challenges; ii) full length CgA directly affects myocardial and coronary function. These results contribute to depict the mechanisms which orchestrate the cardiac sympathochromaffin/CgA axis, and to expand the knowledge on the adrenergic control of the heart under normal conditions and in the presence of stimulation.