Growth-Associated Protein-43 Loss Promotes Ca2+ and ROS Imbalance in Cardiomyocytes

TL;DR

This study shows that the loss of a protein called GAP-43 in heart cells disrupts calcium and reactive oxygen species balance, leading to heart disease risks.

Contribution

The novel contribution is identifying GAP-43's role in regulating Ca2+ and ROS homeostasis in cardiomyocytes, linking its loss to cardiac dysfunction.

Findings

GAP-43−/− cardiomyocytes show increased Ca2+ release and ROS levels.

Treatment with CaM inhibitor W7 or Ru360 reduces ROS and Ca2+ imbalances.

Loss of GAP-43 correlates with cardiac hypertrophy and oxidized proteins.

Abstract

Growth-Associated Protein-43 (GAP-43) is a calmodulin-binding protein, originally found in neurons, that in skeletal muscle regulates the handling of intracellular Ca2+ dynamics. According to its role in Ca2+ regulation, myotubes from GAP-43 knockout (GAP-43−/−) mice display alterations in spontaneous Ca2+ oscillations and increased Ca2+ release. The emerging hypothesis is that GAP-43 regulates CaM interactions with RyR and DHPR Ca2+ 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 Ca2+ 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, Ca2+ alterations, and high mitochondria ROS levels (O2•−) together with increased oxidized functional proteins. Treatment with a CaM inhibitor (W7) restored Ca2+ and ROS alterations, possibly due to high mitochondrial Ca2+ entry by a mitochondrial Ca2+ uniporter. Indeed, Ru360 was able to abolish O2•− mitochondrial production. Our results suggest that GAP-43 has a key role in the regulation of Ca2+ and ROS homeostasis, alterations to which could trigger heart disease.

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