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Published on: August 13, 2019
Membrane Estrogen Receptor β Is Sufficient to Mitigate Cardiac Cell Pathology
Amrita Ahluwalia1, Neil Hoa1, Debbie Moreira1
1Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA.
Insights
Estrogen receptor beta (ERβ) signaling opposes cardiac cell damage. Membrane-bound ERβ is sufficient to prevent angiotensin II-induced cardiac hypertrophy and fibrosis, highlighting its protective role.
Area of Science:
- Cardiovascular Biology
- Molecular Endocrinology
- Cellular Signaling
Background:
- Estrogen receptor beta (ERβ) opposes cardiac hypertrophy and fibrosis.
- ERβ signaling is crucial for estrogen's protective effects on the heart.
- Angiotensin II (AngII) stimulates cardiac cell pathology.
Purpose of the Study:
- To investigate if membrane-bound ERβ is sufficient to counteract AngII-induced cardiac cell pathology.
- To define structural elements of ERβ required for membrane or nuclear localization.
- To assess the necessity and sufficiency of membrane ERβ in mitigating AngII effects.
Main Methods:
- Utilized Chinese hamster ovarian (CHO) cells, mouse and rat myocytes, and cardiac fibroblasts.
- Expressed wild-type (WT) ERβ and C418A-mutant ERβ (lacking palmitoylation site for membrane localization).
- Created an ERβ mutant with a 4-amino acid deletion in the E domain to block nuclear localization.
- Used ERβ-deleted mice to express WT and mutant ERβ constructs in cardiomyocytes and fibroblasts.
Main Results:
- Palmitoylation at cysteine 418 is essential for ERβ membrane localization in various cell types.
- ERβ mutants with blocked nuclear localization retained the ability to oppose AngII-induced cell pathology.
- Estrogen effectively mitigated AngII-stimulated cardiac cell pathology when membrane ERβ was present.
Conclusions:
- Membrane-bound ERβ is sufficient to oppose key mechanisms of AngII-induced cardiac cell pathology.
- ERβ's protective role against AngII can be mediated independently of its nuclear function.
- Targeting membrane ERβ may offer a therapeutic strategy against cardiac hypertrophy and fibrosis.
Abstract:
Estrogen acting through estrogen receptor β (ERβ) has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous work has implicated signal transduction from ERβ as being important to the function of estrogen in this regard. Here we address whether membrane ERβ is sufficient to oppose key mechanisms by which angiotensin II (AngII) stimulates cardiac cell pathology. To do this we first defined essential structural elements within ERβ that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ERβ that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in Chinese hamster ovarian (CHO) cells, and mouse and rat myocytes and cardiac fibroblasts, the effect on multiple aspects of signal transduction by expressing wild-type (WT ) or a C418A-mutant ERβ. To test the importance of the nuclear receptor, we determined a 4-amino acid deletion in the E domain of ERβ that strongly blocked nuclear localization. Using these tools, we expressed WT and mutant ERβ constructs into cardiomyocytes and cardiac fibroblasts from ERβ-deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by AngII and whether the membrane ERβ is necessary and sufficient.
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