Effects of novel estrogen receptor ligands on the myocardium
Project management at the University of Würzburg:
Background: The protective role of estrogens in the cardiovascular system is currently under controversial debate. Studies of our own group as well as other investigators indicate that 17-β estradiol besides its known effects on the vasculature has also direct effects on the myocardium. Previous studies employing an established model of hypertensive heart disease (female spontaneously hypertensive rats; SHR) revealed that:
1. 17-β estradiol directly modulates the expression of contractile proteins in the myocardium (myosin heavy chain α- and β-) that have a pivotal role for cardiac contractility. Estradiol directly upregulated the expression of α-MHC, which differs from β-MHC by its higher ATPase activity and contractility.
2. The anti-hypertensive and anti-hypertrophic effect of ACE-inhibitors, which is significantly reduced by ovarectomy, can be restored by estrogen substitution.
Aims of the study: 17-β estradiol is a non-selective estrogen receptor agonist which binds both estrogen receptor subtypes (α and β) with nearly equal affinity. Furthermore, the use of estradiol is limited due to well known side effects. Novel ligands that selectively bind to the estrogen receptor-α or -β as well as selective estrogen receptor modulators (SERMs) are now available. These compounds may have lesser side effects and could thus be an important step towards future clinical studies. The current study will evaluate the effects of these novel estrogenic compounds on the myocardium which have not been studied so far.
Methods: In analogy to extensive previous studies on 17-β estradiol, the cardiovascular effects of a selective ligand for the estrogen receptor-&alpha, a selective ligand for the estrogen receptor-β and the SERM raloxifene will be evaluated in SHR rats. The animals will be ovarectomized or sham operated and treated with the respective compounds plus / minus an ACE-inhibitor for three months. The analysis will include morphological, molecular and hemodynamic studies of cardiac hypertrophy and myocardial function.
Expected results: The study will clarify the question which estrogen receptor subtype mediates the effects of estradiol on the myocardium observed in previous studies. The study will also determine whether the observed hormone effects on the myocardium modulate cardiac function. As a long term goal, the study should reveal which class of novel estrogenic compounds might be suitable for further and ultimately perhaps clinical studies.
Projekt period: from 05.2002 to 04.2004