The Role of RIPK1 and RIPK3 in Cardiovascular Disease
Abstract
:1. Introduction to RIP1 and RIPK3 and Necroptosis
2. RIPK1 and RIPK3 in Atherosclerosis
3. RIPK1 and RIPK3 in Myocardial Infarction
4. RIPK1 and RIPK3 in Stroke
5. RIPK1 and RIPK3 in Abdominal Aortic Aneurysm
6. RIPK1 and RIPK3 in Thrombosis
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAA | abdominal aortic aneruysm |
ALS | amyotrophic lateral sclerosis |
AngII | angiotensin II |
APOE | apolioprotein E |
CAD | coronary artery disease |
CML | chronic myeloid leukemia |
DAMP | damage-associated molecular patterns |
DVT | deep vein thrombosis |
FADD | FAS-associated death domain |
HIF1α | hypoxia inducible factor-1α |
HUVEC | human umbilical vein endothelial cells |
IFNγ | interferon γ |
IL1β | Interleukin 1β |
IVC | inferior vena cava |
LAD | left anterior descending |
LDL | low-density lipoprotein |
LVEF | left ventricle ejection fraction |
MCAO | middle cerebral artery occlusion |
MI | myocardial infarction |
MLKL | mixed-lineage kinase domain like protein |
MMP | matrix metalloproteinase |
MS | multiple sclerosis |
Nec-1/1s | necrostain-1/1s |
NET | neutrophil extracellular trap |
NFKβ | Nuclear factor kappa β |
NSA | necrosulfonamide |
PCI | percutaneous coronary intervention |
PE | pulmonary embolism |
Ph+ ALL | Philadelphia chromosome positive acute lymphoblastic leukemia |
PI | propidium iodide |
PTLP | phospholipid transfer protein |
RA | rheumatoid arthritis |
RIPK1 | receptor interacting protein kinase 1 |
RIPK3 | receptor interacting protein kinase 3 |
SIRS | systemic inflammatory response syndrome |
SMC | smooth muscle cell |
STEMI | ST elevation myocardial infarction |
STING | stimulator of interferon genes |
TLR 3/4 | toll like receptor 3/4 |
TNFα | tumor necrosis factor α |
TNFR1 | tumor necrosis factor receptor 1 |
TRAILR | tumor necrosis α related apoptosis inducing ligand receptor |
tPA | tissue plasminogen activator |
UC | ulcerative colitis |
VTE | venous thromboembolism |
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Disease | Model/Subjects | Inhibitor | Pertinent Findings | Ref. |
---|---|---|---|---|
Atherosclerosis | Human plaques, Apoe−/− mice, oxLDL BMDM treatment | Nec-1 | RIPK3 and MLKL expression & activation increased in human plaques, Nec-1 reduces plaque size/necrotic core in mice, reduced ox-LDL induced necroptosis in BMDM | [12] |
Atherosclerosis | Human plaques, in vitro serum starvation foam cell model | None | RIPK1/3 expression increased in plaques, serum starvation increases RIPK1/RIPK3 expression, MLKL oligomerization | [19] |
Atherosclerosis | ox-LDL HUVEC treatment | Nec-1 | Ox-LDL increases RIPK1 expression & inflammation, nec-1 ameliorates this effect | [21] |
Atherosclerosis | Ripk3−/−; Ldlr−/− mice, Apoe−/− mice | None | Ripk3−/Ldlr−/− mice−mice have significantly smaller advanced plaques | [22] |
Atherosclerosis | Apoe−/− mice | Anti-sense MLKL oligonucleotides | MLKL knockdown decreased necrotic core size but not plaque size, decreased lipid levels | [26] |
MI | Rat LAD ligation | Nec-1 | RIPK1/RIPK3 increased in cardiac tissue after MI, Nec-1 decreased infarct size | [30] |
MI | Mouse LAD ligation, Ripk3−/− mice | None | RIPK3 increased in cardiac tissue after MI, EF preserved in Ripk3−/− mice after LAD ligation | [31] |
MI | Mouse and rat-derived cardiomyocytes, mouse LAD ligation | Nec-1 | Nec-1 reduced peroxide induced cell death, murine infarct size | [33] |
MI | Mouse LAD ligation | Nec-1 | Nec-1 reduced infarct size, necrotic cell death, prevented adverse remodeling at 28 days | [34] |
MI | Ripk3−/− mice, Mouse LAD ligation | None | Reduced infarct size in Ripk3−/− mice | [35] |
MI | Human STEMI patients | None | In patients with normal troponin on presentation, serum RIPK3 predicts impaired LV function | [41] |
MI | Humans with CAD, angina, unstable angina | None | Plasma RIPK3 correlates with CAD severity | [42] |
Stroke | Mouse MCAO model | Nec-1 | Intracerebroventricular Nec-1 reduced infarct volume | [32] |
Stroke | Oxygen-deprived glucose (ODG) in vitro model, MCAO mouse model | GSK’872 | ODG and MCAO upregulate RIPK1, RIPK3, MLKL, GSK’872 reduces infarct volume | [46] |
Stroke | Rat MCAO model | Nec-1 | Ischemia activates RIPK1/3/MLKL signaling. Nec-1 reduces infarct volume | [47] |
Stroke | Mouse MCAO model, Ripk3−/− mice, Ripk1D138N/D138N mice | None | Inactivation of RIPK1 and absence of RIPK3 can ultimately decrease stroke volume, improve behavioral scores | [48] |
Stroke | Mouse MCAO model, ODG in vitro model, Ripk3−/− and Mlkl−/− mice | None | RIPK3 or MLKL deficiency decreases stroke size, neurologic deficits, polarizes macrophages to M2 phenotype | [49] |
Stroke | Mouse MCAO model, ODG in vitro model | Nec-1 | Nec-1 protects cells from ODG related death, Nec-1 reduced infarct volume | [50] |
Stroke | Mouse MCAO model | NSA | Decreased infarct size, neurologic deficits, MLKL levels; increased MLKL degradation after NSA treatment | [51] |
Stroke | Photothrombosis induced ischemic injury in mouse | Dabrafenib | Dabrafenib reduced infarct size, inflammation | [52] |
AAA | Murine elastase perfusion model, Ripk3−/− mice | None | RIPK1/RIPK3 are locally upregulated in AAA, Ripk3−/− mice are protected from AAA | [58] |
AAA | Murine elastase perfusion model | Nec-1s | Nec-1s slows aneurysm growth, decreases inflammation, preserves vessel architecture | [64] |
AAA | Murine CaCl2 model, murine AngII Apoe−/− model | GSK’074 | GSK’074 can prevent aneurysm growth, preserve vessel architecture in both aneurysm models | [65] |
AAA | Murine CaCl2 model | GSK’074 | GSK’074 slows aneurysm growth, preserves vessel architecture | [66] |
AAA | Murine AngII and CaCl2 model, cell culture | None | STING deficiency decreases necroptosis and protects mice from AAA | [62] |
Arterial thrombosis | Murine FeCl3 injury model, tail bleeding, platelet activity assays, Ripk3−/− mice | None | Ripk3−/− mice have prolonged tail bleeding, FeCl3 arteriole time to occlusion, abnormal dense granule secretion | [76] |
Venous Thrombosis | IVC ligation model, Mlkl−/− mice | Nec-1s, NSA | Nec-1s treatment and MLKL deficiency decrease thrombus size, decrease NETosis. Nec-1s and necrosulfonamide decrease platelet-neutrophil aggregation | [86] |
Inhibitor Name | Molecular Target | Tested Applications | Use in Clinical Trials: Yes/No | Ref. |
---|---|---|---|---|
Necrostatin-1 | RIPK1 | Atherosclerosis §, stroke §, MI § | No | [12,21,30,32,33,34,47,50] |
Necrostatin-1s | RIPK1 | AAA §, venous thrombosis § | No | [64,86] |
PN10 | RIPK1 | TNFα induced SIRS § | No | [87] |
cdp27 | RIPK1 | TNFα induced SIRS § | No | [88] |
GSK′963 | RIPK1 | TNFα induced SIRS § | No | [89] |
RIPA-56 | RIPK1 | TNFα induced SIRS § | No | [90] |
GSK2656157 | RIPK1 | TNFα induced SIRS § | No | [91] |
Sibiriline | RIPK1 | concanavalin A-induced hepatitis § | No | [92] |
GSK’872 | RIPK3 | Stroke §, | No | [46] |
GSK’074 | RIPK1 & RIPK3 | AAA §, | No | [65,66] |
DNL747 | RIPK1 | Alzheimer’s disease, ALS, MS | Yes- Phase I | [87] |
GSK2982772 | RIPK1 | Psoriasis, UC, RA | Yes- Phase II | [93] |
Dabrafenib | RIPK3 | Stroke §, Metastatic melanoma | Yes- Metastatic melanoma, FDA approved | [52,87] |
Ponatinib | RIPK1&RIPK3 | TNFα induced SIRS § | Yes- FDA approved for CML and Ph+ALL | [87,94] |
Sorafenib | RIPK1&RIPK3 | TNFα induced SIRS § and renal ischemia–reperfusion injury § | Yes- FDA approved for advanced liver cancer; renal cancer; thyroid cancer | [95] |
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DeRoo, E.; Zhou, T.; Liu, B. The Role of RIPK1 and RIPK3 in Cardiovascular Disease. Int. J. Mol. Sci. 2020, 21, 8174. https://doi.org/10.3390/ijms21218174
DeRoo E, Zhou T, Liu B. The Role of RIPK1 and RIPK3 in Cardiovascular Disease. International Journal of Molecular Sciences. 2020; 21(21):8174. https://doi.org/10.3390/ijms21218174
Chicago/Turabian StyleDeRoo, Elise, Ting Zhou, and Bo Liu. 2020. "The Role of RIPK1 and RIPK3 in Cardiovascular Disease" International Journal of Molecular Sciences 21, no. 21: 8174. https://doi.org/10.3390/ijms21218174