Sex-specific differences in ventricular expression and function of parathyroid hormone-related peptide.
OBJECTIVE
Parathyroid hormone-related peptide (PTHrP) expression is modulated by estrogen. It is expressed in coronary endothelial cells and involved in the endothelium-dependent regulation of coronary resistance and cardiac function. In the present study, we hypothesized that endogenously synthesized and released PTHrP contributes to sex-specific differences in the regulation of cardiac function.


METHODS
The influence of sex on ventricular PTHrP expression in normotensive rats was determined via real-time PCR and immunoblot analysis. Sex-specific effects of exogenous PTHrP or endogenous released PTHrP were determined in vitro on isolated ventricular cardiomyocytes, Langendorff preparations on isolated hearts and in vivo using different agonistic or antagonistic PTHrP peptides.


RESULTS
Ventricular expression of PTHrP was elevated in hearts from female rats compared to male counterparts. Addition of PTHrP(1-36) did not increase left ventricular function in hearts from either sex, but increased coronary flow in hearts from female rats significantly greater than in those from males. 5Ile-PTHrP(1-36), which was used to antagonize endogenously released PTHrP, reduced left ventricular function in females but not males in vitro and in vivo. Under conditions of increased endogenous PTHrP release, i.e. ischemia-reperfusion, antagonization of PTHrP significantly reduced post-ischemic recovery in hearts from females but not in those from males.


CONCLUSIONS
Sex determines the ventricular expression of PTHrP mRNA and protein. The results indicate that PTHrP may improve cardiac function to a greater extent in women than in men following a brief period of ischemia.
Grohé
Christian
C
Medizinische Universitäts-Poliklinik, Bonn, Germany.
van Eickels
Martin
M
Wenzel
Sibylle
S
Meyer
Rainer
R
Degenhardt
Heike
H
Doevendans
Pieter A
PA
Heinemann
Marcus P
MP
Ross
Günter
G
Schlüter
Klaus-Dieter
KD
D000818:Animals; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005783:Gender Identity; D006352:Heart Ventricles; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010477:Perfusion; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013268:Stimulation, Chemical; D017725:Ventricular Pressure
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; C079957:parathyroid hormone-related peptide (1-36)