Sustained CaMKII activity mediates transient oxidative stress-induced long-term facilitation of L-type Ca2+ current in cardiomyocytes

Abstract

Oxidative stress remodels Ca2+ signaling in cardiomyocytes, which promotes altered heart function in various heart diseases. Ca2+/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 Ca2+ signaling remain unknown. Here, we present evidence demonstrating the role of CaMKII in transient oxidative stress-induced long-term facilitation (LTF) of L-type Ca2+ current (ICa,L) in rat cardiomyocytes. A 5-min exposure of 1mM H2O2 induced an increase in ICa,L, and this increase was sustained for ~1h. The CaMKII inhibitor KN-93 fully reversed H2O2-induced LTF of ICa,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 Ca2+ 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 H2O2 via CaMKII. In conclusion, CaMKII and mitochondria confer oxidative stress-induced pathological cellular memory that leads to cardiac arrhythmia.