Document Detail


Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload.
MedLine Citation:
PMID:  19717730     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that induces myocardial growth in response to several physiological and pathological stimuli. Calcineurin inhibition, induced either via cyclosporine or genetically, can decrease myocardial hypertrophy secondary to pressure overload without affecting left ventricular (LV) systolic function. Since hypertrophy can also affect LV diastolic function, the goal of this study was to examine the effects of chronic pressure overload (2 wk aortic banding) in transgenic (Tg) mice overexpressing Zaki-4beta (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV weight-to-body weight ratio (3.5 + or - 0.1) compared with that in non-Tg mice (4.6 + or - 0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LV end-diastolic stress-to-LV end-diastolic dimension ratio, an index of diastolic stiffness and LV pressure half-time and isovolumic relaxation time, two indexes of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, phosphorylated ryanodine receptor, and the Na(+)/Ca(2+) exchanger were also reduced significantly (P < 0.05) in the banded TgZ mice. As expected, genetic calcineurin inhibition inhibited the development of LV hypertrophy with chronic pressure overload but also induced LV diastolic dysfunction, as reflected by both impaired isovolumic relaxation and increased myocardial stiffness. Thus genetic calcineurin inhibition reveals a new mechanism regulating LV diastolic function.
Authors:
Ricardo J Gelpi; Shumin Gao; Peiyong Zhai; Lin Yan; Chull Hong; Lauren M A Danridge; Hui Ge; Yasahiro Maejima; Martin Donato; Mitsuhiro Yokota; Jeffery D Molkentin; Dorothy E Vatner; Stephen F Vatner; Junichi Sadoshima
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-28
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  297     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-27     Completed Date:  2009-11-12     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1814-9     Citation Subset:  IM    
Affiliation:
Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta / surgery
Calcineurin / antagonists & inhibitors*,  metabolism
Calcium-Binding Proteins / metabolism
Cyclic AMP-Dependent Protein Kinases / metabolism
Diastole* / genetics
Disease Models, Animal
Elasticity
Hypertrophy, Left Ventricular / enzymology,  genetics,  physiopathology,  prevention & control*
Ligation
Mice
Mice, Transgenic
Myocardium / enzymology*
NFATC Transcription Factors / genetics,  metabolism
Phosphorylation
Proteins / genetics,  metabolism*
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Sodium-Calcium Exchanger / metabolism
Stroke Volume
Ventricular Dysfunction, Left / enzymology*,  genetics,  physiopathology
Ventricular Pressure
Grant Support
ID/Acronym/Agency:
AG-014121/AG/NIA NIH HHS; AG-023137/AG/NIA NIH HHS; AG-027211/AG/NIA NIH HHS; HL-033107/HL/NHLBI NIH HHS; HL-059139/HL/NHLBI NIH HHS; HL-067724/HL/NHLBI NIH HHS; HL-069020/HL/NHLBI NIH HHS; HL-069752/HL/NHLBI NIH HHS; R01 HL033107-27/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Dscr1l1 protein, mouse; 0/NFATC Transcription Factors; 0/Proteins; 0/Ryanodine Receptor Calcium Release Channel; 0/Sodium-Calcium Exchanger; 0/phospholamban; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.1.3.16/Calcineurin; EC 3.6.3.8/Atp2a2 protein, mouse; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases
Comments/Corrections

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