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The Estrogen Regulation of Cardiac TRH Gene Expression in Female Rats
Pei Feng, Ph.D.
Dental School, University of Maryland, Baltimore
Thyrotropin-releasing hormone (TRH) from the hypothalamus is the major regulator of TSH synthesis and secretion. The transcription of rat prepro(pp) TRH gene has been identified not only in the hypothalamus, but also in a variety of extra-CNS loci, including, most recently, the heart.
Although knowledge on the biological function of cardiac TRH is limited, previous studies have demonstrated that TRH can stimulate cardiovascular function in endotoxic and hemorrhagic shock animal models. Also, it has been shown that TRH can directly stimulate cardiac contractility in the dog heart, and that testosterone can significantly enhance cardiac TRH gene transcription in male rats. It is known that estrogen, the major sex hormone in females, not only regulates reproductive function, but is also involved in the modulation of cardiovascular functions, especially in the heart. Unlike testosterone levels in the male, estrogen levels change in cycles, falling dramatically after ovarian function failure. However, the potential effect of estrogen on the regulation of cardiac TRH gene expression is not known. Thus the central hypothesis of this proposal is that in the female, estrogen is an important stimulatory regulator for cardiac TRH gene transcription and its encoded proteins, including TRH and TRH- related peptides. The withdrawal of estrogen caused by menopause or surgical castration will affect cardiac TRH gene expression and disturb heart function.
To test this hypothesis, cardiac TRH gene expression in the female rat at different developmental stages will be examined by Northern blot analysis; serum estrogen levels will be measured simultaneously. To identify that cardiac TRH gene expression is estrogen-dependent, cardiac TRH mRNA will be evaluated in in vivo estrogen-treated animal models, and estrogen regulation of TRH gene promoter activities will also be investigated by transfection assays in a heart cell line, H9C2. Concerning the potential biologic functions of cardiac TRH, estrogen regulation of TRH and TRH-related peptides will be determined by Western blot analysis.
The studies proposed herein will provide new insights on the potential estrogen regulation of TRH in an extrahypothalamic locus, the heart. Since cardiovascular disease is one of the most serious diseases in postmenopausal women, the outcome of this new proposal will lead to a better understanding of this phenomena, and may eventually provide new approaches in its prevention and treatment.
