Alcohol Dehydrogenase Protects against Endoplasmic Reticulum Stress-Induced Myocardial Contractile Dysfunction via Attenuation of Oxidative Stress and Autophagy: Role of PTEN-Akt-mTOR Signaling
| Autor: | Rui Guo, Nathan D. Fuller, Nan Hu, Jeremy M. Henion, Jiaojiao Pang, Linzi A. Barton, Jun Ren, Yuguo Chen |
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| Rok vydání: | 2015 |
| Předmět: |
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 |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 1, p e0147322 (2016) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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