CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis
Abstract
Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A few non-canonical instances of pseudonecroptotic RCD involving MLKL (but not RIPK3) or RIPK3 (but not MLKL) have been described.
“Moreover, a few non-canonical instances of pseudonecroptotic RCD involving MLKL (but not RIPK3) [468] or RIPK3 (but not MLKL) [469] have been described.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [469]
Cites
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Myocardial ischemia-reperfusion injury: a neglected therapeutic target
Hausenloy, D. J., & Yellon, D. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62874 · Cited by 2,357 · see citing works
Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., et al. (2005) · Nature · doi:10.1038/nature03434 · Cited by 2,280 · see citing works
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214 · see citing works
Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T., & Tsujimoto, Y. (2005) · Nature · doi:10.1038/nature03317 · Cited by 1,635 · see citing works
Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R. (2011) · Nature · doi:10.1038/nature09852 · Cited by 1,278 · see citing works
RIP3 mediates the embryonic lethality of caspase-8-deficient mice
Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S. (2011) · Nature · doi:10.1038/nature09857 · Cited by 1,057 · see citing works
FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
Welz, P.-S., Wullaert, A., Vlantis, K., Kondylis, V., Fernández-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., & Pasparakis, M. (2011) · Nature · doi:10.1038/nature10273 · Cited by 594 · see citing works
Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury
Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X., & Nagy, L. E. (2013) · Hepatology · doi:10.1002/hep.26200 · Cited by 304 · see citing works
Coupienne, I., Fettweis, G., & Piette, J. (2011) · Lasers in Surgery and Medicine · doi:10.1002/lsm.21088 · Cited by 41 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationInitiation and execution mechanisms of necroptosis: an overview
Grootjans, S., Vanden Berghe, T., & Vandenabeele, P. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.65 · Cited by 566 · see citing works
CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation
Xu, S., Wang, P., Zhang, H., Gong, G., Gutierrez Cortes, N., Zhu, W., Yoon, Y., Tian, R., & Wang, W. (2016) · Nature Communications · doi:10.1038/ncomms13189 · Cited by 218 · see citing works
Zhang, Y., Unnikrishnan, A., Deepa, S. S., Liu, Y., Li, Y., Ikeno, Y., Sosnowska, D., Van Remmen, H., & Richardson, A. (2017) · Redox Biology · doi:10.1016/j.redox.2016.10.014 · Cited by 185 · see citing works
Self-citationWang, Z., Feng, J., Yu, J., & Chen, G. (2019) · Journal of Cell Science · doi:10.1242/jcs.227777 · Cited by 35 · see citing works
- Authors
- Zhang, T., Zhang, Y., Cui, M., Jin, L., Wang, Y., Lv, F., Liu, Y., Zheng, W., Shang, H., Zhang, J., Zhang, M., Wu, H., Guo, J., Zhang, X., Hu, X., Cao, C.-M., & Xiao, R.-P.
- Affiliations
- Peking University (CN)
- Corresponding author
- Zhang, Yan
- Xiao, Rui-Ping
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-01-04
- Volume
- 22
- Issue
- 2
- Pages
- 175-182
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2231291760
- Cited by
- 790
- References
- 10
- Citations by year
- 2026: 55 · 2025: 70 · 2024: 99 · 2023: 88 · 2022: 102 · 2021: 86 · 2020: 85 · 2019: 70 · 2018: 52 · 2017: 49 · 2016: 33
- FWCI
- 35.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Peking University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- CaMKII, RIPK3, necroptosis, myocardial ischemia-reperfusion injury, oxidative stress, heart failure, mitochondrial permeability transition pore, cardiomyocyte death, doxorubicin cardiotoxicity, RIPK1, MLKL, apoptosis, inflammation
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Antibiotics, Antineoplastic, Cell Survival, Doxorubicin, Heart Failure, Immunohistochemistry, Mice, Inbred C57BL, Necrosis, Phosphorylation, Blotting, Western, Myocardial Reperfusion Injury, Myocardial Ischemia, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Microscopy, Confocal, In Situ Nick-End Labeling, Myocytes, Cardiac, Mitochondrial Membrane Transport Proteins, Mice, Rats, Membrane Potential, Mitochondrial, Receptor-Interacting Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
