title: Cardioprotective effects of calcitonin gene-related peptide in isolated rat heart and in H9c2 cells via redox signaling.
abstract: The calcitonin-gene-related-peptide (CGRP) release is coupled to the signaling of Angeli's salt in determining vasodilator effects. However, it is unknown whether CGRP is involved in Angeli's salt cardioprotective effects and which are the mechanisms of protection. We aimed to determine whether CGRP is involved in myocardial protection induced by Angeli's salt. We also analyzed the intracellular signaling pathway activated by CGRP. Isolated rat hearts were pre-treated with Angeli's salt or Angeli's salt plus CGRP8-37, a specific CGRP-receptor antagonist, and subjected to ischemia (30-min) and reperfusion (120-min). Moreover, we studied CGRP-induced protection during oxidative stress (H2O2) and hypoxia/reoxygenation protocols in H9c2 cardiomyocytes. Cell vitality and mitochondrial membrane potential (ΔYm, MMP) were measured using MTT and JC-1 dyes. Angeli's salt reduced infarct size and ameliorated post-ischemic cardiac function via a CGRP-receptor-dependent mechanism. Pre-treatment with CGRP increased H9c2 survival upon challenging with either H2O2(redox stress) or hypoxia/reoxygenation (H/R stress). Under these stress conditions, reduction in MMP and cell death were partly prevented by CGRP. These CGRP beneficial effects were blocked by CGRP8-37.During H/R stress, pre-treatment with either CGRP-receptor, protein kinase C (PKC) or mitochondrial KATPchannel antagonists, and pre-treatment with an antioxidant (2-mercaptopropionylglycine) blocked the protection mediated by CGRP. In conclusion, CGRP is involved in the cardioprotective effects of Angeli's salt. In H9c2 cardiomyocytes, CGRP elicits PKC-dependent and mitochondrial-KATP-redox-dependent mechanisms. Hence, CGRP is an important factor in the redox-sensible cardioprotective effects of Angeli's salt.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tullio
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy. Electronic address: claudia.penna@unito.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy; Department of Veterinary Science, University of Torino, Italy.
authors.forename: Karine
authors.initials: K
authors.lastname: Cabiale
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: Saveria
authors.initials: S
authors.lastname: Femminò
authors.affiliation: Department of Veterinary Science, University of Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Galloni
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy. Electronic address: pasquale.pagliaro@unito.it.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D015221:Potassium Channels / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D015221:Potassium Channels; D020011:Protective Agents; D018015:Receptors, Calcitonin Gene-Related Peptide; C117780:mitochondrial K(ATP) channel; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide
keywords: ATP-sensitive-potassium channels; Hypoxia/Reoxygenation; Mitochondria; Nitroxyl; Protein kinase C; ROS signaling