title: Full-length human chromogranin-A cardioactivity: myocardial, coronary, and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts.
abstract: Plasma chromogranin-A (CgA) concentrations correlate with severe cardiovascular diseases, whereas CgA-derived vasostatin-I and catestatin elicit cardiosuppression via an antiadrenergic/nitric oxide-cGMP mediated mechanism. Whether these phenomena are related is unknown. We here investigated whether and to what extent full-length CgA directly influences heart performance and may be subjected to stimulus-elicited intracardiac processing. Using normotensive and hypertensive rats, we evaluated the following: 1) direct myocardial and coronary effects of full-length CgA; 2) the signal-transduction pathway involved in its action mechanism; and 3) CgA intracardiac processing after β-adrenergic [isoproterenol (Iso)]- and endothelin-1(ET-1)-dependent stimulation. The study was performed by using a Langendorff perfusion apparatus, Western blotting, affinity chromatography, and ELISA. We found that CgA (1-4 nM) dilated coronaries and induced negative inotropism and lusitropism, which disappeared at higher concentrations (10-16 nM). In spontaneously hypertensive rats (SHRs), negative inotropism and lusitropism were more potent than in young normotensive rats. We found that perfusion itself, Iso-, and endothelin-1 stimulation induced intracardiac CgA processing in low-molecular-weight fragments in young, Wistar Kyoto, and SHR rats. In young normotensive and adult hypertensive rats, CgA increased endothelial nitric oxide synthase phosphorylation and cGMP levels. Analysis of the perfusate from both Wistar rats and SHRs of untreated and treated (Iso) hearts revealed CgA absence. In conclusion, in normotensive and hypertensive rats, we evidenced the following: 1) full-length CgA directly affects myocardial and coronary function by AkT/nitric oxide synthase/nitric oxide/cGMP/protein kinase G pathway; and 2) the heart generates intracardiac CgA fragments in response to hemodynamic and excitatory challenges. For the first time at the cardiovascular level, our data provide a conceptual link between systemic and intracardiac actions of full-length CgA and its fragments, expanding the knowledge on the sympathochromaffin/CgA axis under normal and physiopathological conditions.
authors.affiliation: Department of Biology, Ecology, and Earth Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Pasqua
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Stefano
authors.initials: S
authors.lastname: Gentile
authors.forename: Lorena
authors.initials: L
authors.lastname: Pochini
authors.forename: Mimma
authors.initials: M
authors.lastname: Bianco
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Metz-Boutigue
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Cerra
authors.forename: Bruno
authors.initials: B
authors.lastname: Tota
authors.forename: Tommaso
authors.initials: T
authors.lastname: Angelone
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D052636:Allostasis; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D053379:Chromogranin A / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000819:agonists / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006706:Homeostasis; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D053379:Chromogranin A; D019332:Endothelin-1; C506153:chromogranin A, rat