Does protein kinase C play a pivotal role in the mechanisms of ischemic preconditioning?

Abstract

Summary. This communication reviews the evidence for the pivotal role of protein kinase C in ischemic myocardial preconditioning. It is believed that several intracellular signalling pathways via receptor-coupled phospholipase C and its "cross-talk" with phospholipase D converge to activation of protein kinase C isotypes which is followed by phosphorylation of until now (a number of) unknown target proteins which produce the protective state of ischemic preconditioning.After briefly introducing the general biochemical properties of protein kinase C, its isotypes and the limitations of the methodology used to investigate the role of protein kinase C, studies are discussed in which pharmacological inhibition and activation and (immunore)activity and/or isotypes measurements of protein kinase C isotypes were applied to assess the role of activation of protein kinase C in ischemic myocardial preconditioning.It is concluded that definitive proof for the involvement of protein kinase C in preconditioning requires future studies which must focus on the isotype(s) of protein kinase C that are activated, the duration of action, cellular translocation sites and the identity and stability (of covalently bound phosphate) of phosphorylated substrate proteins.Cardiovasc Drugs Ther 1996:10:775-786 Key Words. myocardial ischemia; infarct size; myocardial protection; ischemic preconditioning; protein kinase C; phospholipase C; phospholipase D Ischemic preconditioning is not an organ specific phenomenon, as it does not only occur in the heart [1,2], but also in kidney [3], liver [4] and skeletal muscle [5], while the brain is protected against the consequence of a new ischemic event at 24 hours after the preconditioning stimulus is applied [6]. Furthermore, brief ischemia in organs other than the heart may also limit irreversible damage produced by a subsequent coronary artery occlusion. Thus, in rats a 15-minute occlusion of the mesenteric artery with 10 minutes of reperfusion prior to a 60-minute coronary artery occlusion limited myocardial infarct size by 40% [7]. Since ganglion blockade abolished myocardial protection by mesenteric artery occlusion-reperfusion but not by brief coronary artery occlusion-reperfusion, the mechanism of protection by brief ischemia-reperfusion in other organs appears to differ from that by brief myocardial ischemia-reperfusion [7]. Initially, ischemic preconditioning studies focussed on time characteristics and the search for extracellular endogenous and exogenous factors that either mimicked or inhibited the phenomenon. It proved that protection occurred during two distinct episodes: a classical preconditioning period (CPP) that lasted 2 to 3 hours after the preconditioning stimulus was applied [1,2], and a second window of protection (SWOP) between 24 and 72 hours [8][9][10]. The mechanisms of protection for these two windows are most likely not the same. Rapidly produced endogenous factors may activate intracellular pathways during CPP, while the slower process of induction of heat-shock protei...

New Insights into Cardioprotection by Ischemic Preconditioning and Other Forms of Stressa

“…Nevertheless a large number of potential mediators, such as adenosine receptors, norepinephrine, and activation of (isoenzymes of) protein kinase C, which all ultimately lead to activation of ATP‐sensitive potassium channels, have been suggested to be involved in both phases of protection. 7–13…”

Πειραματική Μελέτη Της Επίδρασης Της Αυξημένης Ενδοκοιλιακής Πίεσης Στην Απόπτωση Των Ηπατοκυττάρων

“…Οι υποδοχείς της αδενοσίνης (Α1) , της νοραδρεναλίνης (α-1) και της βραδυκινίνης ενώνονται με τις πρωτεΐνες-G οι οποίες όταν διεγερθούν αυξάνουν τη δραστηριότητα της φωσφολιπάσης C και D . Τα ένζυμα καταλύουν την υδρόλυση των φωσφολιπιδίων της μεμβράνης με αύξηση των επιπέδων της diacylglycerol και της inositol triphosphate(246) .β) Πρωτεϊνική Κινάση C.H διαγλυκερόλη (diacylglycerol) διεγείρει την πρωτεϊνική κινάση C (PKC), ένα ένζυμο που φαίνεται να παίζει σημαντικό ρόλο στη βιοχημεία της ΙΠ μέσω της φωσφορυλίωσης των δραστικών πρωτεϊνών(247,248). Ο Gotto και συν.…”