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00925njm 22002777a 4500 dc Arcones, Alba C author Martinez-Cignoni, Melanie Raquel author Vila-Bedmar, Rocio author Yanez, Claudia author Lladó, Isabel author Proenza, Ana Maria author Mayor, Federico, Jr author Murga, Cristina author 2021-03 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. Arcones AC, Martinez-Cignoni MR, Vila-Bedmar R, Yanez C, Llado I, Proenza AM, et al. Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones. Cells. 2021 Mar;10(3):673. https://hdl.handle.net/20.500.13003/19479 https://hdl.handle.net/20.500.12105/23251 33803070 10.3390/cells10030673 2073-4409 Cells 2-s2.0-85103862639 633469000001 L2006757942 Sexual dimorphism Cardiovascular disease G protein-coupled receptor kinase 2 Estrogens Mitochondria Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones