Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart

Hideyuki Maeda, Hisashi Nagai, Genzou Takemura, Kaori Shintani-Ishida, Masaaki Komatsu, Sayoko Ogura, Toshihiko Aki, Mikiayasu Shirai, Ichiro Kuwahira, Ken ichi Yoshida

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40 Citations (Scopus)

Abstract

Sleep apnea syndrome (SAS) is considered to be associated with heart failure (HF). It is known that autophagy is induced in various heart diseases thereby promotes survival, but its excess may be maladaptive. Intermittent hypoxia (IH) plays pivotal role in the pathogenesis of SAS. We aimed to clarify the relationships among IH, autophagy, and HF. Rats underwent IH at a rate of 20. cycles/h (nadir of 4% O2 to peak of 21% O2 with 0% CO2) or normal air breathing (control) for 8. h/d for 3. weeks. IH increased the cardiac LC3II/LC3I ratio. The IH induced upregulation of LC3II was attenuated by the administration of an inhibitor of autophagosome formation 3-methyladenine (3-MA), but enhanced by an inhibitor of autophagosome-lysosome fusion chloroquine (CQ), showing enhanced autophagic flux in IH hearts. Electron microscopy confirmed an increase in autophagosomes and lysosomes in IH. With 3-MA or CQ, IH induced progressive deterioration of fractional shortening (FS) on echocardiography over 3. weeks, although IH, 3-MA, or CQ alone had no effects. With CQ, IH for 4. weeks increased serum troponin T levels, reflecting necrosis. Western blotting analyses showed dephosphorylation of Akt and mammalian target of rapamycin (mTOR) at Akt (Ser2448, 2481) sites, suggesting the activation of autophagy via Akt inactivation. Conclusions. IH-mediated autophagy maintains contractile function, whereas when autophagy is inhibited, IH induces systolic dysfunction due to myocyte necrosis. General significance. This study highlighted the potential implications of autophagy in cardio-protection in early SAS patients without comorbidity, reproduced in normal rats by 3~4. weeks of IH.

Original languageEnglish
Pages (from-to)1159-1166
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number8
DOIs
Publication statusPublished - 2013

Keywords

  • Autophagy
  • Heart failure
  • Intermittent hypoxia
  • Sleep apnea syndrome

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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    Maeda, H., Nagai, H., Takemura, G., Shintani-Ishida, K., Komatsu, M., Ogura, S., Aki, T., Shirai, M., Kuwahira, I., & Yoshida, K. I. (2013). Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1832(8), 1159-1166. https://doi.org/10.1016/j.bbadis.2013.02.014