title: pGlu-serpinin protects the normotensive and hypertensive heart from ischemic injury.
abstract: Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-serpinin (pGlu-Serp) are positive cardiac β-adrenergic-like modulators, acting through β1-AR/AC/cAMP/PKA pathway. Because in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition, cardioprotection is often blunted because of the limitations on pro-survival Reperfusion Injury Salvage Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, left ventricular developed pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/Akt, MitoKATP channels and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 cells with pGlu-Serp, which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes that can limit infarct size and overcome the hypertension-induced failure of PostC.
authors.affiliation: Dept of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
authors.forename: T
authors.initials: T
authors.lastname: Pasqua
authors.affiliation: Dept of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
authors.forename: B
authors.initials: B
authors.lastname: Tota
authors.affiliation: Dept of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Penna
authors.affiliation: Tumor Biology and Vascular Targeting Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Corti
authors.affiliation: Dept of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Cerra
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Loh Y
authors.affiliation: Dept of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
authors.forename: T
authors.initials: T
authors.lastname: Angelone
mesh_terms: D000818:Animals; D053379:Chromogranin A / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000150:complications* / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053379:Chromogranin A; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases
keywords: Chromogranin A-derived peptides; hypertension; rat heart; serpinin