Inositol 1,4,5‐trisphosphate Pathway Mediates Testosterone‐Induced Cardiac Hypertrophy

Abstract

The anabolic hormone testosterone is associated with cardiac hypertrophy, but the signal transduction mechanisms involved are poorly known. In this work, primary cultures of neonatal cardiomyocytes where used to study testosterone effects on intracellular Ca2+ and their relation with cardiac hypertrophy markers: β‐MHC and skeletal α‐actin (SKA). Testosterone (100 nM) induced a rapid increase in intracellular Ca2+ that was blocked by inositol 1,4,5‐trisphosphate (IP3) inhibitors (U73122, 2APB and Xestospongin C) or by overexpression of the Ca2+ buffer protein parvalbumin. Neither nifedipine nor ryanodine affected the testosterone‐induced Ca2+ response. Stimulation with testosterone resulted in an increase of β‐MHC (12h) and SKA (24h) expression. Both in the presence of inhibitors of the IP3 pathway or in cells transfected with parvalbumin, β‐MHC and SKA expression were inhibited. Moreover, testosterone induced an increase in NFAT activation measured as luciferase activity that was inhibited by FK506. NFAT inhibition in turn blocked the hypertrophy markers increase. Cyproterone, an inhibitor of androgen receptor, had no effects on the intracellular Ca2+ or NFAT increase, but attenuated β‐MHC and SKA expression. These results suggest a synergism between pathways involving intracellular signal cascades and the classical genomic actions of androgens for testosterone‐induced cardiac hypertrophy.Fondecyt 1060077 FONDAP 15010006