ArticleHypertension (Dallas, Tex. : 1979)2014
Loss of the eukaryotic initiation factor 2α kinase general control nonderepressible 2 protects mice from pressure overload-induced congestive heart failure without affecting ventricular hypertrophy.
Article in Hypertension (Dallas, Tex. : 1979), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
- Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences.Nutrients · 2026Review
- Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.International journal of molecular sciences · 2025Review
- EBBP-Mediated Integrated Stress Response Attenuates Anthracycline-Induced Cardiotoxicity by Inhibiting the Ferroptosis of Cardiomyocytes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.Biology · 2024Article
- General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.Frontiers in aging · 2024Review
- Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis.American journal of respiratory cell and molecular biology · 2023Article
- Mitochondria-associated endoplasmic reticulum membranes (MAMs) and their role in glaucomatous retinal ganglion cell degeneration-a mini review.Frontiers in neuroscience · 2023Review
- A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart.Cardiovascular research · 2022Article
- Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress.Antioxidants (Basel, Switzerland) · 2022Article
- TheFrontiers in genetics · 2022Article
- UPRFrontiers in cell and developmental biology · 2022Review
- Integrated Stress Response Couples Mitochondrial Protein Translation With Oxidative Stress Control.Circulation · 2021Article
- Darier Disease - A Multi-organ Condition?Acta dermato-venereologica · 2021Review
- Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure.International journal of molecular sciences · 2021Review
- Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs).International journal of molecular sciences · 2020Review
- Re-balancing cellular energy substrate metabolism to mend the failing heart.Biochimica et biophysica acta. Molecular basis of disease · 2020Review
- Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases.International journal of molecular sciences · 2020Review
- Mechanical Regulation of Protein Translation in the Cardiovascular System.Frontiers in cell and developmental biology · 2020Review
- Broken heart: A matter of the endoplasmic reticulum stress bad management?World journal of cardiology · 2019Review
- Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart.Frontiers in cardiovascular medicine · 2019Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
In response to several stresses, including nutrient deprivation, general control nonderepressible 2 kinase (GCN2) attenuates mRNA translation by phosphorylating eukaryotic initiation factor 2α(Ser51). Energy starvation is known to exacerbate congestive heart failure, and eukaryotic initiation factor 2α(Ser51) phosphorylation is increased in the failing heart. However, the effect of GCN2 during the evolution of congestive heart failure has not been tested. In this study, we examined the influence of GCN2 expression in response to a cardiac stress by inducing chronic pressure overload with transverse aortic constriction in wild-type and GCN2 knockout mice. Under basal conditions, GCN2 knockout mice had normal left ventricular structure and function, but after transverse aortic constriction, they demonstrated less contractile dysfunction, less increase in lung weight, less increase in lung inflammation and vascular remodeling, and less myocardial apoptosis and fibrosis compared with wild-type mice, despite an equivalent degree of left ventricular hypertrophy. As expected, GCN2 knockout attenuated transverse aortic constriction-induced cardiac eukaryotic initiation factor 2α(Ser51) phosphorylation and preserved sarcoplasmic reticulum Ca(2+) ATPase expression compared with wild-type mice. Interestingly, the expression of the antiapoptotic protein Bcl-2 was significantly elevated in GCN2 knockout hearts, whereas in isolated neonatal cardiomyocytes, selective knockdown of GCN2 increased Bcl-2 protein expression and enhanced myocyte resistance to an apoptotic stress. Collectively, our data support the notion that GCN2 impairs the ventricular adaptation to chronic pressure overload by reducing Bcl-2 expression and increasing cardiomyocyte susceptibility to apoptotic stimuli. Our findings suggest that strategies to reduce GCN2 activity in cardiac tissue may be a novel approach to attenuate congestive heart failure development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.