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

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 20cycles/h (nadir of 4% O2 to peak of 21% O2 with 0% CO2) or normal air breathing (control) for 8h/d for 3weeks. 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 3weeks, although IH, 3-MA, or CQ alone had no effects. With CQ, IH for 4weeks 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 3~4weeks of IH.

• Authors: Hideyuki Maeda, Hisashi Nagai, Genzou Takemura, Kaori Shintani-Ishida, Masaaki Komatsu, Sayoko Ogura, Toshihiko Aki, Mikiayasu Shirai, Ichiro Kuwahira, Ken-ichi Yoshida
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1832 Issue 8 Pg. 1159-66 (Aug 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23499993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Troponin T
• 3-methyladenine
• Chloroquine
• mTOR protein, rat
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Autophagy (drug effects, physiology)
• Chloroquine (pharmacology)
• Heart Diseases (metabolism, pathology, physiopathology)
• Heart Failure (blood, metabolism, physiopathology)
• Hypoxia (metabolism, physiopathology)
• Lysosomes (drug effects, metabolism, physiology)
• Male
• Muscle Contraction (drug effects, physiology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Necrosis (blood, metabolism, physiopathology)
• Phagosomes (drug effects, metabolism, physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• TOR Serine-Threonine Kinases (metabolism)
• Troponin T (blood)