Estrogen and the cardiovascular system

Abstract

Estrogen is a potent steroid with pleiotropic effects, which have yet to be fully elucidated. Estrogen has both nuclear and non-nuclear effects. The rapid response to estrogen, which involves a membrane associated estrogen receptor(ER) and is protective, involves signaling through PI3K, Akt, and ERK 1/2. The nuclear response is much slower, as the ER-estrogen complex moves to the nucleus, where it functions as a transcription factor, both activating and repressing gene expression. Several different ERs regulate the specificity of response to estrogen, and appear to have specific effects in cardiac remodeling and the response to injury. However, much remains to be understood about the selectivity of these receptors and their specific effects on gene expression. Basic studies have demonstrated that estrogen treatment prevents apoptosis and necrosis of cardiac and endothelial cells. Estrogen also attenuates pathologic cardiac hypertrophy. Estrogen may have great benefit in aging as an anti-inflammatory agent. However, clinical investigations of estrogen have had mixed results, and not shown the clear-cut benefit of more basic investigations. This can be explained in part by differences in study design: in basic studies estrogen treatment was used immediately or shortly after ovariectomy, while in some key clinical trials, estrogen was given years after menopause. Further basic research into the underlying molecular mechanisms of estrogen's actions is essential to provide a better comprehension of the many properties of this powerful hormone.

Figure 1

Summary of key known functions of the ER. GPR30’s status as an estrogen receptor remains unresolved. PM -plasma membrane; cyt -cytosol; mito -mitochondrion; nuc -nucleus.

Figure 2

Key genomic changes with ovariectomy in adult heart, aged heart, and aged heart with late estrogen replacement. Increased TNF in aged heart with late replacement only seen at protein level.

Figure 3

Summary of major effects of E2 on vasculature.

Figure 4

Summary of key cardiac effects of E2. Questions remain with regards to the effect of gender vs. estrogen on heart failure. Inhibition of fibrosis and pathologic cardiac hypertrophy is thought to be mediated through ERβ leading to calcineurin degradation.