Loss of CDON aggravates age-related heart damage driven by compromised FOXO3 nuclear localization

Heart disease in elderly is commonly driven by age-related detriment in cardiac structure and function. Cell adhesion associated, oncogene regulated (CDON) plays an important part in heart remodeling and function. However, the involvement of CDON in cardiac aging remains elusive. Here, we determined age-related alteration of cardiac structure and function as well as gene effects in mouse models and cardiomyocytes. Our results showed that aged mice had decreased CDON expression accompanied by cardiac hypertrophy, fibrosis, declined LVEF and LVFS resembling those found in Cdon^+/- mice. Moreover, Cdon^+/- mice presented an increased cardiac expression in molecular aging markers, including cyclin dependent kinase inhibitors p21 and p16, advanced glycation end products, phosphorylated histone H2AX (γH2AX), apoptosis, proinflammatory Il6 and Il1b, senescence-associated beta-galactosidase (SA-β-gal) activity and reactive oxygen species (ROS) level. Likewise, knockdown of Cdon in cardiomyocytes elevated senescence marker level. The senescent cardiomyocytes induced by D-galactose exhibited low expression of CDON, while overexpression of Cdon in D-galactose-treated cells attenuated senescence phenotype. Furthermore, forkhead box O3 (FOXO3) was identified as a CDON-downstream target. Cdon knockdown decreased cytoplasmic but increased nuclear FOXO3 expression. Notably, Cdon deficiency reduced AKT serine/threonine kinase 1 (AKT) phosphorylation, leading to nuclear retention of FOXO3, thereby promoting the growth arrest and DNA damage inducible gamma (Gadd45g) transcription. These effects were implicated in the combination of immunoglobulin (1-5) and fibronectin type III (1) domain of CDON. In conclusion, CDON is pivotal in cardiac aging and may modulate cardiomyocyte senescence through AKT/FOXO3/GADD45G cascade.