Binding of elastin peptides to S‐Gal protects the heart against ischemia/reperfusion injury by triggering the RISK pathway

Abstract

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.

Ginseng protects rodent hearts from acute myocardial ischemia–reperfusion injury through GR/ER-activated RISK pathway in an endothelial NOS-dependent mechanism

“…Accumulated preclinical results clearly show that cardioprotection can be achieved by giving agents that activate the RISK pathway at the time of myocardial ischemia-reperfusion (Robinet et al, 2007;Xin et al, 2010). In the present study, the cardioprotective effect of RSE was demonstrated to be linked to the activation of this RISK pathway.…”

Inflammation in Myocardial Diseases

“…29) or through the production of biologically active chemotactic ECM fragments. 30,31 PARs are a family of G-protein coupled receptors that are activated through the proteolytic cleavage of the N-terminus resulting in the exposure of a tethered ligand, which, in turn, activates the receptor. Four PARs (PAR 1-4) have been identified to date.…”

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production

“…As ERC is involved in EDP-induced signal transduction [7,29,36,37] but also in elastogenesis through tropoelastin binding and secretion [25,38,39], it is of high interest to understand the mechanism leading to its age-related uncoupling.…”