Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function.
Calcineurin is a Ca(2+)/calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.
Hill
Joseph A
JA
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081, USA. joseph-hill@uiowa.edu
Rothermel
Beverly
B
Yoo
Ki-Dong
KD
Cabuay
Barry
B
Demetroulis
Elaine
E
Weiss
Robert M
RM
Kutschke
William
W
Bassel-Duby
Rhonda
R
Williams
R Sanders
RS
D000818:Animals; D001011:Aorta / Q000473:pathology; D001794:Blood Pressure; D015152:Blotting, Northern; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004569:Electroencephalography; D006331:Heart Diseases / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D011312:Pressure; D011485:Protein Binding; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D065095:Calcineurin Inhibitors; D018076:DNA, Complementary; D020033:Protein Isoforms; D012333:RNA, Messenger; D012313:RNA; D019703:Calcineurin