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European Journal of Heart Failure 2007 9(12):1156-1162; doi:10.1016/j.ejheart.2007.10.007
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© 2007 European Society of Cardiology

Parathyroid hormone-related protein (PTHrP) signal cascade modulates myocardial dysfunction in the pressure overloaded heart

Rainer Meyera, Rolf Schreckenbergb, Frank Kretschmera, Anne Bittiga, Charlotte Conzelmannb, Christian Grohéc and Klaus-Dieter Schlüterb,*

a Physiologisches Institut II, Universitätsklinikum Bonn Germany
b Justus-Liebig-Universität, Physiologisches Institut Aulweg 129, D-35392 Giessen, Germany
c Medizinische Universitäts-Poliklinik Universitätsklinikum Bonn, Germany

* Corresponding author. Tel.: +49 641 99 47 212; fax: +49 641 99 47 219. Klaus-Dieter.Schlueter{at}physiologie.med.uni-giessen.de


  Abstract

Background: Pressure overload induces the cardiac expression of parathyroid hormone-related protein (PTHrP). Plasma levels are elevated in patients with heart disease. It is unknown whether this represents an epiphenomenon or suggests involvement in hypertrophy.

Aim: To identify a potential role of PTHrP in pressure induced hypertrophy and heart failure.

Methods and results: Pressure load was produced via thoracic aortic constriction (TAC) and application of a PTHrP antagonist (PTHrP(7–34)) via osmotic minipumps in mice. Main findings were confirmed in vitro by exposing isolated adult ventricular mice cardiomyocytes to PTHrP(1–34) (100 nmol/l). TAC treated animals developed myocardial hypertrophy within 2 weeks. The heart weight to body weight ratio increased from 5.02±0.14 mg/g (sham/vehicle) and 5.16±0.19 mg/g (sham/antagonist) to 6.59±0.85 mg/g (TAC/vehicle) and 7.07±0.80 mg/g (TAC/antagonist) (each n=6–8; p<0.05 for TAC vs. sham; not significantly different between TAC groups). In parallel, the expression of atrial natriuretic factor increased. Cardiac dysfunction (+dP/dt, –dP/dt), however, was significantly lower in TAC mice receiving the antagonist, and SERCA2 expression was higher. Isolated cardiomyocytes exposed to PTHrP(1–34) developed reduced cell shortening. This reduction in cell function was abolished in the co-presence of the antagonist.

Conclusion: PTHrP contributes to the progression of cardiac dysfunction in the pressure overloaded heart.

Key Words: SERCA • Diastolic function • Myocardial hypertrophy

Received July 6, 2007; Revised August 22, 2007; Accepted October 18, 2007


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