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Sustained CaMKII activity mediates transient oxidative stress-induced long-term facilitation of L-type Ca(2+) current in cardiomyocytes.
MedLine Citation:
PMID:  21854842     Owner:  NLM     Status:  Publisher    
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.
Young-Hwan Song; Euna Choi; Sun-Hyun Park; Suk-Ho Lee; Hana Cho; Won-Kyung Ho; Shin-Young Ryu
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-5
Journal Detail:
Title:  Free radical biology & medicine     Volume:  -     ISSN:  1873-4596     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine, Seoul 139-707, Republic of Korea.
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