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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/H1814    most recent 00449.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gelpi, R. J. Articles by Sadoshima, J. PubMed PubMed Citation Articles by Gelpi, R. J. Articles by Sadoshima, J.

Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload

¹Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey; ²Institute of Cardiovascular Physiopathology and the Department of Pathology, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina; ³Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan; and ⁴Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, and the Howard Hughes Medical Institute, Cincinnati, Ohio

Submitted May 14, 2009 ; accepted in final form August 18, 2009

Calcineurin is a Ca²⁺/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-4β (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 ± 0.1) compared with that in non-Tg mice (4.6 ± 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 Ca²⁺-ATPase 2a, phosphorylated ryanodine receptor, and the Na⁺/Ca²⁺ 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.

hypertrophy; diastole; hemodynamics