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

• Autores: Gelpi, Ricardo Jorge; Gao, Shumin; Zhai, Peiyong; Yan, Lin; Hong, Chull; Danridge, Lauren M. A.; Ge, Hui; Maejima, Yasahiro; Donato, Martin Alejandro; Yokota, Mitsuhiro; Molkentin, Jeffery D.; Vatner, Dorothy E.; Vatner, Stephen F.; Sadoshima, Junichi
• Año de publicación: 2009
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: hypertrophy; Diastole; Hemodynamics
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload. Am J Physiol Heart Circ Physiol 297: H1814 –H1819, 2009. First published August 28, 2009; doi:10.1152/ajpheart.00449.2009.—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-4 (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.
Fil: Gelpi, Ricardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Gao, Shumin. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Zhai, Peiyong. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Yan, Lin. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Hong, Chull. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Danridge, Lauren M. A.. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Ge, Hui. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Maejima, Yasahiro. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Donato, Martin Alejandro. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Yokota, Mitsuhiro. Aichi Gakuin University; Japón
Fil: Molkentin, Jeffery D.. University of Cincinnati; Estados Unidos
Fil: Vatner, Dorothy E.. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Vatner, Stephen F.. University of Medicine and Dentistry of New Jersey; Estados Unidos
Fil: Sadoshima, Junichi. University of Medicine and Dentistry of New Jersey; Estados Unidos