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.