PMID- 34572045
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20220506
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 9
DP  - 2021 Sep 12
TI  - MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis.
LID - 10.3390/cells10092397 [doi]
LID - 2397
AB  - Receptor interacting protein kinase 3 (RIPK3)-mediated smooth muscle cell (SMC) 
      necroptosis has been shown to contribute to the pathogenesis of abdominal aortic 
      aneurysms (AAAs). However, the signaling steps downstream from RIPK3 during SMC 
      necroptosis remain unknown. In this study, the roles of mixed lineage kinase 
      domain-like pseudokinase (MLKL) and calcium/calmodulin-dependent protein kinase 
      II (CaMKII) in SMC necroptosis were investigated. We found that both MLKL and 
      CaMKII were phosphorylated in SMCs in a murine CaCl(2)-driven model of AAA and 
      that Ripk3 deficiency reduced the phosphorylation of MLKL and CaMKII. In vitro, 
      mouse aortic SMCs were treated with tumor necrosis factor alpha (TNFalpha) plus Z-VAD-FMK 
      (zVAD) to induce necroptosis. Our data showed that both MLKL and CaMKII were 
      phosphorylated after TNFalpha plus zVAD treatment in a time-dependent manner. SiRNA 
      silencing of Mlkl-diminished cell death and administration of the CaMKII 
      inhibitor myristoylated autocamtide-2-related inhibitory peptide (Myr-AIP) or 
      siRNAs against Camk2d partially inhibited necroptosis. Moreover, knocking down 
      Mlkl decreased CaMKII phosphorylation, but silencing Camk2d did not affect 
      phosphorylation, oligomerization, or trafficking of MLKL. Together, our results 
      indicate that both MLKL and CaMKII are involved in RIPK3-mediated SMC 
      necroptosis, and that MLKL is likely upstream of CaMKII in this process.
FAU - Zhou, Ting
AU  - Zhou T
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
FAU - DeRoo, Elise
AU  - DeRoo E
AUID- ORCID: 0000-0003-1440-317X
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
FAU - Yang, Huan
AU  - Yang H
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
FAU - Stranz, Amelia
AU  - Stranz A
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
FAU - Wang, Qiwei
AU  - Wang Q
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
FAU - Ginnan, Roman
AU  - Ginnan R
AD  - Department of Molecular and Cellular Physiology, Albany Medical College, Albany, 
      NY 12208, USA.
FAU - Singer, Harold A
AU  - Singer HA
AD  - Department of Molecular and Cellular Physiology, Albany Medical College, Albany, 
      NY 12208, USA.
FAU - Liu, Bo
AU  - Liu B
AD  - Department of Surgery, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53705, USA.
AD  - Department of Cellular and Regenerative Biology, School of Medicine and Public 
      Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
LA  - eng
GR  - R01 HL049426/HL/NHLBI NIH HHS/United States
GR  - R01 HL149404/HL/NHLBI NIH HHS/United States
GR  - 17POST33680095/American Heart Association/
GR  - R01 HL088447/HL/NHLBI NIH HHS/United States
GR  - T32 HL110853/HL/NHLBI NIH HHS/United States
GR  - 20CDA35350009/American Heart Association/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210912
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.- (MLKL protein, mouse)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ripk3 protein, mouse)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - M4I0D6VV5M (Calcium Chloride)
SB  - IM
MH  - Animals
MH  - Aortic Aneurysm, Abdominal/chemically induced/metabolism/*pathology
MH  - Calcium Chloride/toxicity
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocytes, Smooth Muscle/metabolism/*pathology
MH  - *Necrosis
MH  - Phosphorylation
MH  - Protein Kinases/chemistry/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/*physiology
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC8471540
OTO - NOTNLM
OT  - CaMKII
OT  - MLKL
OT  - abdominal aortic aneurysm
OT  - necroptosis
OT  - smooth muscle cells
COIS- The authors declare no conflict of interest.
EDAT- 2021/09/29 06:00
MHDA- 2021/11/23 06:00
PMCR- 2021/09/12
CRDT- 2021/09/28 01:04
PHST- 2021/08/19 00:00 [received]
PHST- 2021/09/06 00:00 [revised]
PHST- 2021/09/08 00:00 [accepted]
PHST- 2021/09/28 01:04 [entrez]
PHST- 2021/09/29 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2021/09/12 00:00 [pmc-release]
AID - cells10092397 [pii]
AID - cells-10-02397 [pii]
AID - 10.3390/cells10092397 [doi]
PST - epublish
SO  - Cells. 2021 Sep 12;10(9):2397. doi: 10.3390/cells10092397.