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Alcohol Dehydrogenase Protects against Endoplasmic Reticulum Stress-Induced Myocardial Contractile Dysfunction via Attenuation of Oxidative Stress and Autophagy: Role of PTEN-Akt-mTOR Signaling
- Source :
- PLoS ONE, PLoS ONE, Vol 11, Iss 1, p e0147322 (2016)
- Publication Year :
- 2015
-
Abstract
- Background The endoplasmic reticulum (ER) plays an essential role in ensuring proper folding of the newly synthesized proteins. Aberrant ER homeostasis triggers ER stress and development of cardiovascular diseases. ADH is involved in catalyzing ethanol to acetaldehyde although its role in cardiovascular diseases other than ethanol metabolism still remains elusive. This study was designed to examine the impact of ADH on ER stress-induced cardiac anomalies and underlying mechanisms involved using cardiac-specific overexpression of alcohol dehydrogenase (ADH). Methods ADH and wild-type FVB mice were subjected to the ER stress inducer tunicamycin (1 mg/kg, i.p., for 48 hrs). Myocardial mechanical and intracellular Ca(2+) properties, ER stress, autophagy and associated cell signaling molecules were evaluated. Results ER stress compromised cardiac contractile function (evidenced as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca(2+) homeostasis), oxidative stress and upregulated autophagy (increased LC3B, Atg5, Atg7 and p62), along with dephosphorylation of PTEN, Akt and mTOR, all of which were attenuated by ADH. In vitro study revealed that ER stress-induced cardiomyocyte anomaly was abrogated by ADH overexpression or autophagy inhibition using 3-MA. Interestingly, the beneficial effect of ADH was obliterated by autophagy induction, inhibition of Akt and mTOR. ER stress also promoted phosphorylation of the stress signaling ERK and JNK, the effect of which was unaffected by ADH transgene. Conclusions Taken together, these findings suggested that ADH protects against ER stress-induced cardiac anomalies possibly via attenuation of oxidative stress and PTEN/Akt/mTOR pathway-regulated autophagy.
- Subjects :
- 0301 basic medicine
lcsh:Medicine
Cardiovascular Medicine
medicine.disease_cause
Endoplasmic Reticulum
Biochemistry
Mice
Ventricular Dysfunction, Left
Cell Signaling
Medicine and Health Sciences
Transgenes
Phosphorylation
Post-Translational Modification
lcsh:Science
Ultrasonography
Multidisciplinary
Secretory Pathway
Cell Death
TOR Serine-Threonine Kinases
Tunicamycin
Physics
Classical Mechanics
Animal Models
Endoplasmic Reticulum Stress
Signaling Cascades
Cell biology
Cell Processes
Cardiovascular Diseases
Physical Sciences
Mechanical Stress
Signal transduction
Cellular Structures and Organelles
Signal Transduction
Research Article
MAP Kinase Signaling System
Recombinant Fusion Proteins
Autophagic Cell Death
ATG5
Mice, Inbred Strains
Mice, Transgenic
Mouse Models
Biology
Research and Analysis Methods
Stress Signaling Cascade
03 medical and health sciences
Model Organisms
medicine
Autophagy
Animals
Protein kinase B
PI3K/AKT/mTOR pathway
Sirolimus
Endoplasmic reticulum
Adenine
Myocardium
lcsh:R
Alcohol Dehydrogenase
PTEN Phosphohydrolase
Biology and Life Sciences
Proteins
Cell Biology
Myocardial Contraction
Oxidative Stress
030104 developmental biology
Unfolded protein response
lcsh:Q
Calcium
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
Oxidative stress
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....dfc8fd373b197b79a06c5405842b4ae1