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


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


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.


CONCLUSIONS
PTHrP contributes to the progression of cardiac dysfunction in the pressure overloaded heart.
Meyer
Rainer
R
Physiologisches Institut II, Universitätsklinikum Bonn, Germany.
Schreckenberg
Rolf
R
Kretschmer
Frank
F
Bittig
Anne
A
Conzelmann
Charlotte
C
Grohé
Christian
C
Schlüter
Klaus-Dieter
KD
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017725:Ventricular Pressure / Q000502:physiology
D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger