ER-BETA SELECTIVE AGONIST CORONARY PROTECTION IN MENOPAUSE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This Phase II SBIR project continues with studies of rhesus monkeys in vivo to further test, and develop toward approval as a drug for human use, a novel estrogen receptor beta (ER-Beta) selective (over ER-alpha) agonist that is hypothesized to be effective for maintaining function of coronary arteries and also for relieving vasomotor symptoms of steroid deficiency and hormonal imbalance. The new drug will be formulated with the aim of protection of coronary arteries against hyperreactivity as a proactive step to reduce the incidence of coronary dysfunction in both women and men. The designated indication, to reduce coronary hyperreactivity, is hypothesized to result from deficiencies in steroid hormones and the imbalance of ER-Beta/ER-alpha stimulation that develops with hypogonadal function, menopause, and in the normal aging process. Dimera in vivo cardiac catheterization and in vitro primary VMC (vascular muscle cell) cultures have pioneered tests for effectiveness in preventing hyperreactivity. PanVera ER¿ fluorescence polarization analysis adds genomic regulation dimensions to the plan. The newly discovered endogenous ER-Beta Agonist (ER-Beta-A) will be studied in adult female and male rhesus (M. mulatta) in the catheterization laboratory, and in VMC isolated from rhesus coronary arteries. The effectiveness of the new ER-Beta-A in preventing coronary hyperreactivity will be assessed by an established protocol based on responses to vasoconstrictor challenges during angiography. Tissue Factor Pathway Inhibitor (TFPI) levels will be measured as an index of protection against thromboembolism. In addition, C-Reactive Protein (CRP) in serum and thromboxane B2 in urine will be used as adverse indicators. Histopathology and Ki67 immunocytochemistry will be included to determine whether there are effects of the ER-Beta-A on breast or uterine (or prostate in males) cell proliferation. Isolated coronary vascular muscle cells will be studied to investigate receptor roles in related protective actions on Ca2-plus and PKC signals.