Binding of elastin peptides to S-Gal protects the heart against ischemia/reperfusion injury by triggering the RISK pathway.
Elastin peptides (EPs) generated by hydrolysis of elastic fibers by elastinolytic enzymes display a wide spectrum of biological activities. Here, we investigated their influence on rat heart ischemia-mediated injury using the Langendorff ex vivo model. EPs, i.e., kappa elastin, at 1.32- and 660-nM concentrations, when administered before the ischemia period, elicited a beneficial influence against ischemia by accelerating the recovery rate of heart contractile parameters and by decreasing significantly creatine kinase release and heart necrosis area when measured at the onset of the reperfusion. All effects were S-Gal-dependent, as being reproduced by (VGVAPG)3 and as being inhibited by receptor antagonists, such as lactose and V14 peptide (VVGSPSAQDEASPL). EPs interaction with S-Gal triggered NO release and activation of PI3-kinase/Akt and ERK1/2 in human coronary endothelial cells (HCAECs) and rat neonatal cardiomyocytes (RCs). This signaling pathway, as designated as RISK, for reperfusion injury salvage kinase pathway, was shown to be responsible for the beneficial influence of EPs on ischemia/reperfusion injury on the basis of its inhibition by specific pharmacological inhibitors. EPs survival activity was attained at a concentration averaging that present into the blood circulation, supporting the contention that these matrikines might offer a natural protection against cardiac injury in young and adult individuals. Such protective effect might be lost with aging, since we found that hearts from 24-month-old rats did not respond to EPs.
Robinet
Arnaud
A
Laboratoire de Pharmacologie Médicale, Université de Reims-Champagne-Ardenne, Faculté de Médecine, Reims, France.
Millart
Hervé
H
Oszust
Floriane
F
Hornebeck
William
W
Bellon
Georges
G
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004549:Elastin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006321:Heart / Q000254:growth & development; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D008969:Molecular Sequence Data; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017725:Ventricular Pressure / Q000187:drug effects; D001616:beta-Galactosidase / Q000502:physiology*
D002316:Cardiotonic Agents; D016895:Culture Media, Serum-Free; D010446:Peptide Fragments; D009569:Nitric Oxide; D004549:Elastin; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001616:beta-Galactosidase