© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy
aCardiovascular Research Institute, Department of Cell Biology and Molecular Medicine and Department of Medicine, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Medical Science Building. G-609 UMDNJ P.O. Box 1709, 185 South Orange Avenue, Newark, NJ 07101, USA
bDepartment of Medicine, University of Queensland, The Prince Charles Hospital, Brisbane, Qld 4032, Australia
vatnersf{at}umdnj.edu
* Corresponding author. Tel.: +1-973-972-8920; fax: +1-973-972-7489.
Objective: The calcineurin pathway has been involved in the development of cardiac hypertrophy, yet it remains unknown whether calcineurin activity can be regulated in myocardium independently from hypertrophy and cardiac load. Methods: To test that hypothesis, we measured calcineurin activity in a rat model of infrarenal aortic constriction (IR), which affects neurohormonal pathways without increasing cardiac afterload. Results: In this model, there was no change in arterial pressure over the 4-week experimental period, and the left ventricle/body weight ratio did not increase. At 2 weeks after IR, calcineurin activity was increased 1.8-fold (P<0.05) and remained elevated at 4 weeks (1.7-fold, P<0.05). Similarly, the cardiac activity of calcium calmodulin kinase II (CaMKII) was increased significantly after IR, which confirms a regulation of Ca2+-dependent enzymes in this model. In cardiac myocytes, the increased activity of calcineurin was accompanied by a significant decrease in L-type Ca2+ channel activity (ICa) and contraction velocity (–dL/dt). Cardiac denervation prevented the activation of calcineurin after IR, which demonstrates that a neurohormonal mechanism is responsible for the changes in enzymatic activity. In addition, cardiac denervation suppressed the effects of IR on ICa and –dL/dt, which shows that calcineurin activation is related to altered contractility. However, action potential duration, the densities of inward rectifier K+ currents (IK1), and outward K+ currents (Ito and IK) were not altered in IR myocytes. Conclusions: Calcineurin can be activated in the heart through a neural stimulus, which induces alterations in Ca2+ currents and contractility. These effects occur in the absence of myocyte hypertrophy, electrophysiological changes in action potential, and K+ channel currents.
KEYWORDS Autonomic nervous system; Calcium (cellular); Contractile function; Hypertrophy; Signal transduction
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. D. Garciarena, O. A. Pinilla, M. B. Nolly, R. P. Laguens, E. M. Escudero, H. E. Cingolani, and I. L. Ennis Endurance Training in the Spontaneously Hypertensive Rat: Conversion of Pathological into Physiological Cardiac Hypertrophy Hypertension, April 1, 2009; 53(4): 708 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kilic, A. Velic, L. J. De Windt, L. Fabritz, M. Voss, D. Mitko, M. Zwiener, H. A. Baba, M. van Eickels, E. Schlatter, et al. Enhanced Activity of the Myocardial Na+/H+ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor-Deficient Mice Circulation, October 11, 2005; 112(15): 2307 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D Molkentin Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs Cardiovasc Res, August 15, 2004; 63(3): 467 - 475. [Abstract] [Full Text] [PDF]
|
|