Key result
PI3K/AKT/mTOR inhibition reverses isoproterenol-induced cardiac injury, oxidative stress, and apoptosis in Takotsubo rat models.
Why the study?
Takotsubo syndrome is a stress-induced cardiomyopathy, but the accurate cause remains unknown.
Does PI3K/AKT/mTOR inhibition reduce oxidative stress and cardiac dysfunction in a preclinical model of Takotsubo syndrome?
Does PI3K/AKT/mTOR inhibition reduce oxidative stress and cardiac dysfunction in a preclinical model of Takotsubo syndrome?
Inhibition of the PI3K/AKT/mTOR pathway protects against isoproterenol-induced cardiac injury and oxidative stress in a preclinical model of Takotsubo syndrome.
Does not support clinical use in Takotsubo syndrome; leaves open translation of PI3K/AKT/mTOR inhibition to humans.
INTRODUCTION: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, but the accurate cause of this syndrome is still unknown. METHODS: β-adrenergic agonist isoproterenol (ISO) is used to establish the TTS rats model. TTS rats were treated with or without LY294002 or Rapamycin. The rat cardiomyoblast cell line H9C2 was subjected to infect with constitutively active Akt (myr-Akt) or dominant-negative mutant Akt (dn-Akt) and then, treated with ISO. Cell apoptosis was assessed using the Bax/ Bcl-2 ratio. In addition, reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE). Mitochondrial superoxide generation and membrane potential were assayed by MitoSOX and JC-1 fluorescence intensity. RESULTS: ISO might induce the erratic acute cardiac dysfunction and overexpression of PI3K/AKT/mTOR. Moreover, it also increased the oxidative stress and apoptosis in TTS rats. The Akt inhibitor significantly reversed the cardiac injury effect, which triggered by ISO treatment. In H9C2 cells, the inhibition of Akt provides a protective role against ISO-induced injury by reducing oxidative stress, apoptosis and mitochondrial dysfunction. CONCLUSION: This study provided new insight into the protective effects of myocardial dysfunction in TTS rats via chronic inhibition of the PI3K/AKT/mTOR expression, which could reduce mitochondrial ROS and oxidative stress-induced apoptosis. PI3K/AKT/mTOR inhibitor could be a therapeutic target to treat cardiovascular dysfunction induced by stress cardiomyopathy.
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Shan et al. (2019) studied Takotsubo syndrome. LY294002 or Rapamycin (PI3K/AKT/mTOR inhibitors) vs. Isoproterenol without inhibitors was evaluated on Cardiac dysfunction, oxidative stress, and apoptosis. Inhibition of the PI3K/AKT/mTOR pathway reversed isoproterenol-induced cardiac injury, oxidative stress, and apoptosis in Takotsubo syndrome rat models and H9C2 cells.
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