Bevere Michele, Morabito Caterina, Verucci Delia, Di Sinno Noemi, Mariggiò Maria A, Guarnieri Simone
Department of Neuroscience, Imaging and Clinical Sciences and Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.
ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy.
Antioxidants (Basel). 2025 Mar 19;14(3):361. doi: 10.3390/antiox14030361.
Growth-Associated Protein-43 (GAP-43) is a calmodulin-binding protein, originally found in neurons, that in skeletal muscle regulates the handling of intracellular Ca dynamics. According to its role in Ca regulation, myotubes from GAP-43 knockout (GAP-43) mice display alterations in spontaneous Ca oscillations and increased Ca release. The emerging hypothesis is that GAP-43 regulates CaM interactions with RyR and DHPR Ca channels. The loss of GAP-43 promotes cardiac hypertrophy in newborn GAP-43 mice, extending the physiological role of GAP-43 in cardiac muscle. We investigated the role of GAP-43 in cardiomyocytes derived from the hearts of GAP-43 mice, evaluating intracellular Ca variations and the correlation with the levels of reactive oxygen species (ROS), considering their importance in cardiovascular physiology. In GAP-43 cardiomyocytes, we found the increased expression of markers of cardiac hypertrophy, Ca alterations, and high mitochondria ROS levels (O) together with increased oxidized functional proteins. Treatment with a CaM inhibitor (W7) restored Ca and ROS alterations, possibly due to high mitochondrial Ca entry by a mitochondrial Ca uniporter. Indeed, Ru360 was able to abolish O mitochondrial production. Our results suggest that GAP-43 has a key role in the regulation of Ca and ROS homeostasis, alterations to which could trigger heart disease.
生长相关蛋白43（GAP - 43）是一种钙调蛋白结合蛋白，最初在神经元中发现，在骨骼肌中可调节细胞内钙动力学的处理。根据其在钙调节中的作用，来自GAP - 43基因敲除（GAP - 43）小鼠的肌管在自发钙振荡方面表现出改变，且钙释放增加。新出现的假说是，GAP - 43调节钙调蛋白与兰尼碱受体（RyR）和二氢吡啶受体（DHPR）钙通道的相互作用。GAP - 43的缺失会促进新生GAP - 43小鼠的心脏肥大，这扩展了GAP - 43在心肌中的生理作用。我们研究了GAP - 43在源自GAP - 43小鼠心脏的心肌细胞中的作用，评估细胞内钙的变化以及与活性氧（ROS）水平的相关性，同时考虑到它们在心血管生理学中的重要性。在GAP - 43心肌细胞中，我们发现心脏肥大标志物的表达增加、钙改变以及线粒体ROS水平升高（O），同时氧化的功能蛋白也增加。用钙调蛋白抑制剂（W7）处理可恢复钙和ROS的改变，这可能是由于线粒体钙单向转运体导致线粒体钙大量内流所致。事实上，钌红（Ru360）能够消除O线粒体的产生。我们的结果表明，GAP - 43在钙和ROS稳态的调节中起关键作用，其改变可能引发心脏病。
