title: Phosphodiesterase type-2 and NO-dependent S-nitrosylation mediate the cardioinhibition of the antihypertensive catestatin.
abstract: The chromogranin A (CHGA)-derived peptide catestatin (CST: hCHGA(352-372)) is a noncompetitive catecholamine-release inhibitor that exerts vasodilator, antihypertensive, and cardiosuppressive actions. We have shown that CST directly influences the basal performance of the vertebrate heart where CST dose dependently induced a nitric oxide-cGMP-dependent cardiosuppression and counteracted the effects of adrenergic stimulation through a noncompetitive antagonism. Here, we sought to determine the specific intracardiac signaling activated by CST in the rat heart. Physiological analyses performed on isolated, Langendorff-perfused cardiac preparations revealed that CST-induced negative inotropism and lusitropism involve β(2)/β(3)-adrenergic receptors (β(2)/β(3)-AR), showing a higher affinity for β(2)-AR. Interaction with β(2)-AR activated phosphatidylinositol 3-kinase/endothelial nitric oxide synthase (eNOS), increased cGMP levels, and induced activation of phosphodiesterases type 2 (PDE2), which was found to be involved in the antiadrenergic action of CST as evidenced by the decreased cAMP levels. CST-dependent negative cardiomodulation was abolished by functional denudation of the endothelium with Triton. CST also increased the eNOS expression in cardiac tissue and human umbilical vein endothelial cells. cells, confirming the involvement of the vascular endothelium. In ventricular extracts, CST increased S-nitrosylation of both phospholamban and β-arrestin, suggesting an additional mechanism for intracellular calcium modulation and β-adrenergic responsiveness. We conclude that PDE2 and S-nitrosylation play crucial roles in the CST regulation of cardiac function. Our results are of importance in relation to the putative application of CST as a cardioprotective agent against stress, including excessive sympathochromaffin overactivation.
authors: Department of Cell Biology, Laboratory of Cardiovascular Pathophysiology, University of Calabria, Arcavacata di Rende (CS), Italy. t.angelone@unical.it
authors: Tommaso
authors: T
authors: Angelone
authors: Anna Maria
authors: AM
authors: Quintieri
authors: Teresa
authors: T
authors: Pasqua
authors: Stefano
authors: S
authors: Gentile
authors: Bruno
authors: B
authors: Tota
authors: Sushil K
authors: SK
authors: Mahata
authors: Maria Carmela
authors: MC
authors: Cerra
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D053379:Chromogranin A / Q000494:pharmacology*; D005092:Exonucleases / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins; D000099211:Phospholamban
chemical_list: D000959:Antihypertensive Agents; D019390:Arrestins; D002135:Calcium-Binding Proteins; D002317:Cardiovascular Agents; D053379:Chromogranin A; D005092:Exonucleases; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D011943:Receptors, Adrenergic, beta; D000071557:beta-Arrestins; D000099211:Phospholamban; C109084:chromogranin A (344-364); C022650:spleen exonuclease