Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 304, Issue 6, Pages H828-H839Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00752.2012
Keywords
endoplasmic reticulum; calcium/calmodulin-activated protein kinase II; apoptosis
Funding
- National Institutes of Health [5P20-RR-016474, 8P20-GM-103432]
Ask authors/readers for more resources
Roe ND, Ren J. Oxidative activation of Ca2+/calmodulin-activated kinase II mediates ER stress-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol 304: H828-H839, 2013. First published January 11, 2013; doi:10.1152/ajpheart.00752.2012.-Endoplasmic reticulum (ER) stress elicits oxidative stress and intracellular Ca2+ derangement via activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This study was designed to examine the role of CaMKII in ER stress-induced cardiac dysfunction and apoptosis as well as the effect of antioxidant catalase. Wild-type FVB and transgenic mice with cardiac-specific overexpression of catalase were challenged with the ER stress inducer tunicamycin (3 mg/kg ip for 48 h). Presence of ER stress was verified using the ER stress protein markers immunoglobulin binding protein (BiP) and C/EBP homologous protein (CHOP), the effect of which was unaffected by catalase overexpression. Echocardiographic assessment revealed that tunicamycin elicited cardiac remodeling (enlarged end-systolic diameter without affecting diastolic and ventricular wall thickness), depressed fractional shortening, ejection fraction, and cardiomyocyte contractile capacity, intracellular Ca2+ mishandling, accumulation of reactive oxygen species (superoxide production and NADPH oxidase p47phox level), CaMKII oxidation, and apoptosis (evidenced by Bax, Bcl-2/Bax ratio, and TUNEL staining), the effects of which were obliterated by catalase. Interestingly, tunicamycin-induced cardiomyocyte mechanical anomalies and cell death were ablated by the CaMKII inhibitor KN93, in a manner reminiscent of catalase. These data favored a permissive role of oxidative stress and CaMKII activation in ER stress-induced cardiac dysfunction and cell death. Our data further revealed the therapeutic potential of antioxidant or CaMKII inhibition in cardiac pathological conditions associated with ER stress. This research shows for the first time that contractile dysfunction caused by ER stress is a result of the oxidative activation of the CaMKII pathway.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available