title: Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload.
abstract: 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.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.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Gelpi
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Lauren M A
authors.initials: LM
authors.lastname: Danridge
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.forename: Yasahiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Martin
authors.initials: M
authors.lastname: Donato
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003971:Diastole / Q000235:genetics; D004195:Disease Models, Animal; D004548:Elasticity; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017725:Ventricular Pressure; D000099211:Phospholamban
chemical_list: D019703:Calcineurin; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D011506:Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C486303:Dscr1l1 protein, mouse; C506947:Atp2a2 protein, mouse