Myocardial Akt activation and gender - Increased nuclear activity in females versus males

Cardiovascular disease risk is higher in men than women, but the basis for this discrepancy remains controversial. Estrogenic stimulation of the myoca rdium or isolated cardiomyocytes has been purported to exert multiple benef icial effects associated with inhibition of maladaptive responses to pathog enic insults. This report describes a significant difference between the se xes in myocardial activation of Akt, a protein kinase that regulates a broa d range of physiological responses including metabolism, gene transcription , and cell survival. We find that young women possess higher levels of nucl ear-localized phospho-Akt(473) relative to comparably aged men or postmenop ausal women. Both localization of phospho-Akt(473) in myocardial nuclei of sexually mature female mice versus males and Akt kinase activity in nuclear extracts of hearts from female mice versus males are elevated. Cytosolic l ocalization of phospho-forkhead, a downstream nuclear target of Akt, is als o increased in female relative to male mice, suggesting a potential mechani sm for cardioprotective nuclear signaling resulting from Akt activation. Ph ospho-Akt(473) levels and localization at cardiac nuclei are similarly incr eased in transgenic mice with myocardium-specific expression of insulin-lik e growth factor I, a proven stimulus for Akt activation. Phospho-Akt(473) i s also localized to the nucleus of cultured cardiomyocytes after exposure t o 17 beta -estradiol or genistein (a phytoestrogen in soy protein-based die ts), and neonatal exposure of litters to genistein elevated nuclear phospho -Akt(473) localization, The activation of Akt in a gender-dependent manner may help explain differences observed in cardiovascular disease risk betwee n the sexes and supports the potential beneficial effects of estrogenic sti mulation.