title: Sustained CaMKII activity mediates transient oxidative stress-induced long-term facilitation of L-type Ca(2+) current in cardiomyocytes.
abstract: Oxidative stress remodels Ca(2+) signaling in cardiomyocytes, which promotes altered heart function in various heart diseases. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was shown to be activated by oxidation, but whether and how CaMKII links oxidative stress to pathophysiological long-term changes in Ca(2+) signaling remain unknown. Here, we present evidence demonstrating the role of CaMKII in transient oxidative stress-induced long-term facilitation (LTF) of L-type Ca(2+) current (I(Ca,L)) in rat cardiomyocytes. A 5-min exposure of 1mM H(2)O(2) induced an increase in I(Ca,L), and this increase was sustained for ~1h. The CaMKII inhibitor KN-93 fully reversed H(2)O(2)-induced LTF of I(Ca,L), indicating that sustained CaMKII activity underlies this oxidative stress-induced memory. Simultaneous inhibition of oxidation and autophosphorylation of CaMKII prevented the maintenance of LTF, suggesting that both mechanisms contribute to sustained CaMKII activity. We further found that sarcoplasmic reticulum Ca(2+) release and mitochondrial ROS generation have critical roles in sustaining CaMKII activity via autophosphorylation- and oxidation-dependent mechanisms. Finally, we show that long-term remodeling of the cardiac action potential is induced by H(2)O(2) via CaMKII. In conclusion, CaMKII and mitochondria confer oxidative stress-induced pathological cellular memory that leads to cardiac arrhythmia.
authors.affiliation: Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine, Seoul 139-707, Republic of Korea.
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Song
authors.forename: Euna
authors.initials: E
authors.lastname: Choi
authors.forename: Sun-Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Suk-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Ho
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Ryu
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006861:Hydrogen Peroxide; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides