Abstract
This study was designed to evaluate the role of ULK1 in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. Wild-type and AMPK knockout mice were challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial function was evaluated using echocardiography and edge-detection. Western blot analysis was employed to evaluate the levels of AMPK, Raptor, mTOR, the AMPK downstream signal ULK1 and autophagy markers Beclin-1 and LC3-II. siRNA was used to knockdown ULK1 in H9C2 myoblasts. GFP-LC3 puncta was used to evaluate autophagosome formation. Alcohol challenge compromised cardiac function as evidenced by decreased fractional shortening, peak shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay in WT mice, the effects of which were mitigated by AMPK knockout. Ethanol exposure facilitated myocardial autophagy as evidenced by enhanced LC3-II level, as well as phosphorylation of AMPK, Raptor, and dephosphorylation of mTOR and ULKI in WT hearts, which were alleviated by AMPK knockout. Pharmacological inhibition of AMPK using compound C attenuated ethanol-induced autophagosome formation, AMPK phosphorylation, ULK1 dephosphorylation and apoptosis. Ethanol exposure-induced cardiomyocyte contractile defects and autophagosome accumulation were reversed by the autophagy inhibitor 3-MA. Similarly, knockdown of ULK1 using siRNA in H9C2 cells ablated ethanol-induced autophagosome accumulation, LC3-II expression and cell death. Lysosomal inhibition using bafilomycin, E64-D and pepstatin A potentiated ethanol-induced increase in autophagosome formation. Taken together, our results suggest that ULK1 may play a critical role in AMPK-mediated myocardial autophagy, apoptosis and contractile dysfunction following acute alcohol challenge.
Keywords: Alcohol, cardiac function, autophagy, AMPK, ULK1.
Current Pharmaceutical Design
Title:ULK1 Plays a Critical Role in AMPK-Mediated Myocardial Autophagy and Contractile Dysfunction following Acute Alcohol Challenge
Volume: 19 Issue: 27
Author(s): Machender R. Kandadi, Nan Hu and Jun Ren
Affiliation:
Keywords: Alcohol, cardiac function, autophagy, AMPK, ULK1.
Abstract: This study was designed to evaluate the role of ULK1 in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. Wild-type and AMPK knockout mice were challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial function was evaluated using echocardiography and edge-detection. Western blot analysis was employed to evaluate the levels of AMPK, Raptor, mTOR, the AMPK downstream signal ULK1 and autophagy markers Beclin-1 and LC3-II. siRNA was used to knockdown ULK1 in H9C2 myoblasts. GFP-LC3 puncta was used to evaluate autophagosome formation. Alcohol challenge compromised cardiac function as evidenced by decreased fractional shortening, peak shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay in WT mice, the effects of which were mitigated by AMPK knockout. Ethanol exposure facilitated myocardial autophagy as evidenced by enhanced LC3-II level, as well as phosphorylation of AMPK, Raptor, and dephosphorylation of mTOR and ULKI in WT hearts, which were alleviated by AMPK knockout. Pharmacological inhibition of AMPK using compound C attenuated ethanol-induced autophagosome formation, AMPK phosphorylation, ULK1 dephosphorylation and apoptosis. Ethanol exposure-induced cardiomyocyte contractile defects and autophagosome accumulation were reversed by the autophagy inhibitor 3-MA. Similarly, knockdown of ULK1 using siRNA in H9C2 cells ablated ethanol-induced autophagosome accumulation, LC3-II expression and cell death. Lysosomal inhibition using bafilomycin, E64-D and pepstatin A potentiated ethanol-induced increase in autophagosome formation. Taken together, our results suggest that ULK1 may play a critical role in AMPK-mediated myocardial autophagy, apoptosis and contractile dysfunction following acute alcohol challenge.
Export Options
About this article
Cite this article as:
Kandadi R. Machender, Hu Nan and Ren Jun, ULK1 Plays a Critical Role in AMPK-Mediated Myocardial Autophagy and Contractile Dysfunction following Acute Alcohol Challenge, Current Pharmaceutical Design 2013; 19 (27) . https://dx.doi.org/10.2174/1381612811319270010
DOI https://dx.doi.org/10.2174/1381612811319270010 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
From Mars to Venus: Gender Differences in the Management and Outcomes of Acute Coronary Syndromes
Current Pharmaceutical Design Non-glycemic Adverse Effects of Insulin
Current Diabetes Reviews Radioligands for the Angiotensin II Subtype 1 (AT1) Receptor
Current Topics in Medicinal Chemistry Clinical Applications and Biosafety of Human Adult Mesenchymal Stem Cells
Current Pharmaceutical Design Left Ventricular Non-compaction: From Recognition to Treatment
Current Pharmaceutical Design Inflammatory Markers Associated With Diabetes Mellitus – Old and New Players
Current Pharmaceutical Design Plant Extracts and Isolated Compounds Reduce Parameters of Oxidative Stress Induced by Heavy Metals: An up-to-Date Review on Animal Studies
Current Pharmaceutical Design Animal Modeling of Cancer Pathology and Studying Tumor Response to Therapy
Current Drug Targets Fetal Risks of Maternal Diabetes
Current Women`s Health Reviews Editorial: [Hot Topic: Chromogranin A at the Crossroads of Health and Disease]
Current Medicinal Chemistry Preface
Current Cardiology Reviews A Practical Guide for the Treatment of Symptomatic Heart Failure with Reduced Ejection Fraction (HFrEF)
Current Cardiology Reviews MicroRNAs: Biomarkers for Cardiovascular Disease in Patients with Diabetes Mellitus
Current Topics in Medicinal Chemistry Hydroximic Acid Derivatives: Pleiotropic Hsp Co-Inducers Restoring Homeostasis and Robustness
Current Pharmaceutical Design Withdrawal Notice: Therapeutic Options for Treatment of COVID-19: A Review from Repurposed Drugs to New Drug Targets
Current Drug Targets Cardioprotection by Targeting the Pool of Resident and Extracardiac Progenitors
Current Drug Targets Cardioprotective Effects of Natural Products <i>via</i> the Nrf2 Signaling Pathway
Current Vascular Pharmacology Annexin A5 Imaging: An Academic Research – Clinical Trials and Theses
Current Molecular Imaging (Discontinued) GRK2 Inhibition in Heart Failure: Something Old, Something New
Current Pharmaceutical Design Biochemical Markers of Cardiovascular Damage from Tobacco Smoke
Current Pharmaceutical Design