Abstract
Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.
Highlights
We found that the G protein-coupled receptor kinase 2 (GRK2) protein levels present with sexual dimorphism in the young animals and with a sexdependent differential modulation with age
Since GRK2 has recently been shown to modulate mitochondrial function in the heart [27,36], and mitochondrial fusion markers in High Fat Diet (HFD)fed male mice inversely relate to cardiac GRK2 levels [31], we analyzed the isoform processing of optic atrophy (OPA1) as a readout of mitochondrial fusion capacity [37]
We determined that aging induces an increase in GRK2 levels in the heart only in female mice, and that cardiac GRK2 protein levels are sensitive to ovarian hormones
Summary
Cardiovascular disease (CVD) constitutes a global burden and stands as the leading cause of morbidity and mortality worldwide [1,2] Among women, it is the premier cause of death in the United States [3]. Incidences of cardiovascular pathologies are lower in pre-menopausal women compared to age-matched men. Among the mechanisms implicated in age-dependent sensitivity to CVD, the mitochondrial dynamics stand out as a key modulator of cardiac output [16,17,18]. We describe unforeseen sex- and age-dependent patterns of GRK2 modulation in the murine heart which parallel the differential sensitivity described in the development of CVD. Age-dependent GRK2 protein upregulation in females can be recapitulated by the loss of ovarian hormones and are partly reverted by estrogen supplementation, mediators that may lay at the basis of the sexual dimorphism observed in cardiac GRK2 dynamics
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