Growth Associated Protein-43 Loss Promotes Cardiac Hypertrophy Through Ca2+ and ROS Imbalance

Growth Associated Protein-43 (GAP-43) is a calmodulin-binding protein, originally found in neurons, that in skeletal muscle regulates handlings of intracellular Ca2+ dynamics. According to its role in Ca2+ regulation, myotubes from GAP-43-null mice display alterations in spontaneous Ca2+ oscillations and evoked Ca2+ release. Emerging hypothesis is that GAP-43 regulates CaM interac-tions with RyR and DHPR Ca2+ channels. Loss of GAP-43 promotes cardiac hypertrophy in new-born knockout mice, extending the physiological role of GAP43 in cardiac muscle. We investigated the role of GAP-43 in cardiomyocytes deriving from GAP-43 knockout (GAP-43-/-) mice, evaluating intracellular Ca2+ variation and its correlation with the levels of reactive oxygen species (ROS), considering their importance in cardiovascular physiology. In GAP-43-/- cardiomyocytes we found increased expression of markers of cardiac hypertrophy, Ca2+ alterations and high mitochondria ROS levels (O2.¯) together with increased oxidized functional proteins. The treatment with a CaM inhibitor (W7) restored Ca2+ and ROS alterations possibly due to high mitochondrial Ca2+ entry by mitochondrial Ca2+ uniporter. Indeed, Ru360 was able to abolish the O2.¯ mitochondrial production. Our results suggest that GAP-43 has a key role in the regulation of Ca2+ and ROS homeostasis, whose alterations could trigger heart disease.