Membrane Estrogen Receptor β Is Sufficient to Mitigate Cardiac Cell Pathology.

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.