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

GELPI RJ; GAO S; ZHAI P; YAN L; HONG C; DANRIDGE L; GE H; MAEJIMA Y; DONATO M; YOKOTA M; MOLKENTIN J; VATNER D; VATNER SF; SADOSHIMA J

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY

HighWire Press

Año: 2009 vol. 297 p. 1814 - 1819

0363-6135

Calcineurin is a calcium/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 wks aortic banding) in transgenic (Tg) mice overexpressing Zaki-4 (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. Methods and Results: As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV/body weight (3.5±0.1) compared with non-Tg (NTg) mice (4.6±0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LVED Stress/LVEDD ratio, an index of diastolic stiffness and T½ and isovolumic relaxation time, two indices of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), SERCA2a, phosphorylated ryanodine receptor and the Na+/Ca2+ exchanger were also reduced significantly, p<0.05, in the banded TgZ mice. Conclusions: 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.