Calmodulin kinase II inhibition disrupts cardiomyopathic effects of enhanced green fluorescent protein.
Transgenic expression of enhanced green fluorescent protein (eGFP) in myocardium can result in cardiac dysfunction and cardiomyopathy, presumably through toxic effects that disrupt normal cellular signaling. The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is widely expressed in myocardium and CaMKII activity is increased in human and animal models of cardiomyopathy, so we hypothesized that increased CaMKII activity is important for cardiomyopathy due to transgenic expression of eGFP. Here we report that cardiomyocyte-delimited eGFP over-expression causes increased CaMKII activity that predicts left ventricular dilation and dysfunction. On the other hand, transgenic co-expression of a CaMKII inhibitory peptide with eGFP prevents eGFP-mediated left ventricular dilation and dysfunction. These findings suggest that increased CaMKII activity is a critical pathological signal in transgenic cardiomyopathy due to eGFP over-expression.
Khoo
Michelle S C
MS
Department of Internal Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Grueter
Chad E
CE
Eren
Mesut
M
Yang
Jinying
J
Zhang
Rong
R
Bass
Martha A
MA
Lwin
Seint T
ST
Mendes
Lisa A
LA
Vaughan
Douglas E
DE
Colbran
Roger J
RJ
Anderson
Mark E
ME
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D009202:Cardiomyopathies / Q000201:enzymology* / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D010455:Peptides; C405629:autocamtide 3; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2