The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
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
Open accessAbstract
Rationale: Autophagy 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. Objective: We investigated whether Nox4 is involved in the regulation of autophagy and cell survival during energy stress in cardiomyocytes. Methods and Results: Production 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. Conclusions: Nox4 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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Cites
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865
Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4
Scherz‐Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601623 · Cited by 2,101 · cited 2×
“Intracellular ROS levels increase in response to energy deprivation.(17,18) However, exactly where and how ROS are produced and how ROS affect autophagy and survival of cardiomyocytes during energy deprivation remains to be elucidated.”
BackgroundDefective Hepatic Autophagy in Obesity Promotes ER Stress and Causes Insulin Resistance
Yang, L., Li, P., Fu, S., Calay, E. S., & Hotamisligil, G. S. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.04.005 · Cited by 1,274
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NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
Kuroda, J., Ago, T., Matsushima, S., Zhai, P., Schneider, M. D., & Sadoshima, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002178107 · Cited by 772
Self-citationAgo, T., Kuroda, J., Pain, J., Fu, C., Li, H., & Sadoshima, J. (2010) · Circulation Research · doi:10.1161/circresaha.109.213116 · Cited by 506
Self-citationDifferential Roles of GSK-3β During Myocardial Ischemia and Ischemia/Reperfusion
Zhai, P., Sciarretta, S., Galeotti, J., Volpe, M., & Sadoshima, J. (2011) · Circulation Research · doi:10.1161/circresaha.111.249532 · Cited by 218 · cited 1×
“Finally, autophagy is protective during fasting and prolonged ischemia, but it was reported to be detrimental during pressure overload when it promoted maladaptive hypertrophy(39) and during reperfusion damage.(5,33) Therefore, it is possible that Nox4 activation is both protective during energy deprivation and detrim…”
BackgroundSelf-citationOxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor
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Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival
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Cited by
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585
Self-citationFundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease
Del Re, D. P., Amgalan, D., Linkermann, A., Liu, Q., & Kitsis, R. N. (2019) · Physiological Reviews · doi:10.1152/physrev.00022.2018 · Cited by 961
Functions of ROS in Macrophages and Antimicrobial Immunity
Herb, M., & Schramm, M. (2021) · Antioxidants · doi:10.3390/antiox10020313 · Cited by 633
The Role of Autophagy in the Heart
Sciarretta, S., Maejima, Y., Zablocki, D., & Sadoshima, J. (2018) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021317-121427 · Cited by 547
Self-citationShirakabe, A., Zhai, P., Ikeda, Y., Saito, T., Maejima, Y., Hsu, C.-P., Nomura, M., Egashira, K., Levine, B., & Sadoshima, J. (2016) · Circulation · doi:10.1161/circulationaha.115.020502 · Cited by 466
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Metadata
- Authors
- Sciarretta, S., Zhai, P., Shao, D., Zablocki, D., Nagarajan, N., Terada, L. S., Volpe, M., & Sadoshima, J.
- Venue
- Circulation Research
- Published
- 2013-11-08
- Volume
- 113
- Issue
- 11
- Pages
- 1253-1264
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2159156984
- Cited by
- 192
- References
- 10
- FWCI
- 10.81
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Sciarretta, S., Zhai, P., Shao, D., Zablocki, D., Nagarajan, N., Terada, L. S., Volpe, M., & Sadoshima, J. (2013). 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. Circulation Research. https://doi.org/10.1161/circresaha.113.301787
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