A talk with Ellis R. Levin, MD about ENDO abstract Estrogen Action on Cardiac Myocytes and Fibroblasts
What are the highlights that attendees should take away from your presentation?
Estrogen acts exclusively through estrogen receptor beta (ERbeta) to oppose the ability of angiotensin II or endothelin I to strongly stimulate cardiomyocyte hypertrophy and heart failure in-vivo in mouse models. Estrogen also blocks hypertension-stimulation in the mice over four weeks by angiotensin administration. This is also due to action at ERbeta in blood vessels due to the stimulation of nitric oxide formation in arteries, causing vasodilation.
Estrogen acts exclusively to block angiotensin II-induced transition of cardiac fibroblasts in-vivo and in-vitro to myofibroblasts. There are multiple pathways that angiotensin II stimulates through transforming growth factor beta (TGF-beta) in these cells, importantly phosphorylating and stimulating a resulting nuclear translocation of SMAD 1 and 3 transcription factors as one aspect. These transcription factors are essential for collagen genes and other pro-fibrotic proteins expression in myofibroblasts that are critical for human cardiac and mouse heart fibrosis. Estrogen signals through AMP kinase, protein kinase A, and other kinases to block the effects of TGF-beta and downstream targets, thus preventing fibrosis by 95% in-vivo.
What is the central question that your study and/or presentation tries to answer?
We have recently described the site of palmitoylation of ERbeta that is required for the movement of this sex steroid receptor to the plasma membrane. By making a mutant of the cysteine palmitoylation site to alanine, we show the importance of the membrane-localized ERbeta, explaining how estrogen causes kinase activation from this receptor pool. The membrane-localized pool of ERbeta is a G-protein-coupled receptor. This is critical to estrogen action in these regards above. Importantly, estrogen acts normally in both wild-type and estrogen receptor alpha (ERalpha) knockout mice, but the estrogen effects described above are completely lost when ERbeta is deleted in-vivo (mice) or in-vitro.
If applicable, what are the key findings from your study?
Estrogen has strong effects on all these parameters mentioned above, acting through signal transduction caused by membrane ERbeta. We have also defined key structural elements that are required for the nuclear localization of ERbeta. We are currently exploring mutations of the ERbeta gene that codes for the amino acids, which are needed for nuclear translocation, to determine its role in the effects of estrogen. The effects of estrogen and ERbeta block 95% of the angiotensin/TGF-beta induced fibrosis in the heart of mice. This is likely for effects of estrogen/ERbeta to block pulmonary fibrosis and to understand the known effects of estrogen to block inflammation-induced liver fibrosis and progression to cirrhosis (liver failure). Thus what we define in the heart is likely applicable to other organs.
How do these findings and/or conclusions potentially impact clinical practice?
These effects do not involve estrogen acting at ERalpha that can cause estrogen responses to stimulate breast and uterine cancer. There are no highly selective ERbeta agonists used in clinical medicine. Such a drug could be potentially used in clinical trials on women who have predispositions to developing the diseases mentioned previously. This might be an impetus for pharmaceutical companies to develop and test such a drug. Such a drug would not stimulate the cancers mentioned above. Soy extracts often bind to ERbeta, and perhaps that could be used in clinical practice.