ArticleCirculation research2013
Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 pathway.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 1 of them a synthesis that pooled it.
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Who cites it
114 citing papers in PubMed, 1 synthesis or guideline pooled it, 184 citations in OpenAlex.
- NADPH oxidases in Parkinson's disease: a systematic review.Molecular neurodegeneration · 2017Pooled it
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- Inhibition of SUR1-TRPM4 attenuates astrocyte swelling and reactivity under oxygen-glucose deprivation/reoxygenation.PloS one · 2026Article
- Nicotinamide adenine dinucleotide phosphate oxidase 4 in lung disease: a review of its biology and therapeutic potential.Experimental biology and medicine (Maywood, N.J.) · 2026Review
- MacrophageAutophagy · 2025Article
- Cancer Cell-Derived Large Extracellular Vesicles Promote Venous Thromboembolism by Activating NETosis Through Delivering CYBA.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Dual Role of NOX4 in Cardiovascular Diseases: Driver of Oxidative Stress and Mediator of Adaptive Remodeling.Antioxidants (Basel, Switzerland) · 2025Review
- p22Nature cardiovascular research · 2025Article
- Review
- Exploring the potential regulation of DUOX in thyroid hormone‑autophagy signaling via IGF‑1 in the skeletal muscle (Review).Biomedical reports · 2025Review
- The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer.International journal of molecular sciences · 2025Review
- Targeting NLRC5 in cardiomyocytes protects postinfarction cardiac injury by enhancing autophagy flux through the CAVIN1/CAV1 axis.Communications biology · 2025Article
- The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.Autophagy reports · 2025Review
- Role of AMPK and Sirtuins in Aging Heart: Basic and Translational Aspects.Aging and disease · 2024Review
- Mammalian integrated stress responses in stressed organelles and their functions.Acta pharmacologica Sinica · 2024Review
- Article
- Role of Oxygen and Its Radicals in Peripheral Nerve Regeneration: From Hypoxia to Physoxia to Hyperoxia.International journal of molecular sciences · 2024Review
- CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.Experimental & molecular medicine · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
rationaleAutophagy is an essential survival mechanism during energy stress in the heart. Oxidative stress is activated by energy stress, but its role in mediating autophagy is poorly understood. NADPH oxidase (Nox) 4 is an enzyme that generates reactive oxygen species (ROS) at intracellular membranes. Whether Nox4 acts as a sensor of energy stress to mediate activation of autophagy is unknown.
objectiveWe investigated whether Nox4 is involved in the regulation of autophagy and cell survival during energy stress in cardiomyocytes. METHODS AND
resultsProduction of ROS in cardiomyocytes was increased during glucose deprivation (GD) in a Nox4-dependent manner. Protein levels and the ROS-producing activity of Nox4 were increased in the endoplasmic reticulum (ER), but not in mitochondria, in response to GD. Selective knockdown of Nox4, but not Nox2, or selective reduction of ROS in the ER with ER-targeted catalase, but not mitochondria-targeted perioxiredoxin 3, abrogated GD-induced autophagy. Nox4 promoted autophagy during GD through activation of the protein kinase RNA-activated-like ER kinase pathway by suppression of prolyl hydroxylase 4. The decrease in cell survival during GD in the presence of Nox4 knockdown was rescued by reactivation of autophagy by Atg7 overexpression, indicating that the effect of Nox4 on cell survival is critically mediated through regulation of autophagy. Nox4 was activated during fasting and prolonged ischemia in the mouse heart, where Nox4 is also required for autophagy activation and cardioprotection.
conclusionsNox4 critically mediates autophagy in response to energy stress in cardiomyocytes by eliciting ROS in the ER and stimulating the protein kinase RNA-activated-like ER kinase signaling pathway.
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