Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

© 2021 by the authors.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.We acknowledge support by the Agencia Estatal de Investigación (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and grant SAF2016-80384 R to ILL and AMP); the CIBER de Enfermedades Cardiovasculares (CIBERCV, Instituto de Salud Carlos III) Spain (grant CB16/11/00278 to F.M., co-funded with European FEDER contribution), and the Programa de Actividades en Biomedicina de la Comunidad de Madrid (B2017/BMD-3671-INFLAMUNE to FM). MR M-C was funded by a grant from Balearic Islands Government (FPI/1888/2016), after being selected in the framework of an operating program co-financed by the European Social Fund.Peer reviewe