Comparative Proteomic Analysis Reveals Sex and Estrogen Receptor β Effects in the Pressure Overloaded Heart

In pressure overload (PO), sex differences
in humans and rodents
have been well documented and estrogen receptor (ER) β is considered
cardioprotective. However, the underlying mechanisms are poorly understood.
Our aim was to investigate sex- and ERβ-specific effects in
protein abundance in PO employing a 2-dimensional gel electrophoresis/mass
spectrometry-based proteomics approach. We hypothesized major sex
differences and ERβ-specific alterations consistent with cardioprotection
in females. Two-month old male and female wild-type (WT) and ERβ
knockout (BERKO) mice were subjected to transverse aortic constriction
(TAC) for 9 weeks (n = 4/group). In WT mice, hypertrophy
was significantly more pronounced in males than females, while this
sex difference was abolished in BERKO mice. We found 82 protein spots
modulated between TAC and sham in WT males, 31 in WT females, 114
in BERKO males, and 87 in BERKO females (P ≤
0.05). Our analysis revealed in WT and BERKO females an altered pattern
of various proteins involved in structure and suggests a link between
female sex and cytoskeletal integrity. In males, a set of proteins
was identified that associate with mitochondrial bioenergetics and
energy supply. We confirmed protein regulation by immunoblotting analysis.
In conclusion, the proteomic response of the heart to PO is significantly
modulated by ERβ and sex. We put forward that the observed differences
may identify sex-specific targets for the treatment of heart failure,
contributing toward more personalized medical care.