PMID- 29127238
OWN - NLM
STAT- MEDLINE
DCOM- 20190107
LR  - 20230816
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 314
IP  - 3
DP  - 2018 Mar 1
TI  - Protective effects of the mechanistic target of rapamycin against excess iron and 
      ferroptosis in cardiomyocytes.
PG  - H659-H668
LID - 10.1152/ajpheart.00452.2017 [doi]
AB  - Clinical studies have suggested that myocardial iron is a risk factor for left 
      ventricular remodeling in patients after myocardial infarction. Ferroptosis has 
      recently been reported as a mechanism of iron-dependent nonapoptotic cell death. 
      However, ferroptosis in the heart is not well understood. Mechanistic target of 
      rapamycin (mTOR) protects the heart against pathological stimuli such as 
      ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated 
      cell death, we examined cardiomyocyte (CM) cell viability under excess iron and 
      ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR 
      transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were 
      treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis 
      inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. 
      Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 
      induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, 
      inhibited cell death in all conditions. mTOR overexpression suppressed 
      Fe(III)-citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion 
      exaggerated cell death in these conditions. 2',7'-Dichlorodihydrofluorescein 
      diacetate measurement of reactive oxygen species (ROS) production showed that 
      erastin-induced ROS production was significantly lower in mTOR transgenic versus 
      control CMs. These findings suggest that ferroptosis is a significant type of 
      cell death in CMs and that mTOR plays an important role in protecting CMs against 
      excess iron and ferroptosis, at least in part, by regulating ROS production. 
      Understanding the effects of mTOR in preventing iron-mediated cell death will 
      provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY 
      Ferroptosis has recently been reported as a new form of iron-dependent 
      nonapoptotic cell death. However, ferroptosis in the heart is not well 
      characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that 
      the mechanistic target of rapamycin plays an important role in protecting 
      cardiomyocytes against excess iron and ferroptosis.
FAU - Baba, Yuichi
AU  - Baba Y
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
AD  - Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University , 
      Kochi , Japan.
FAU - Higa, Jason K
AU  - Higa JK
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Shimada, Briana K
AU  - Shimada BK
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Horiuchi, Kate M
AU  - Horiuchi KM
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Suhara, Tomohiro
AU  - Suhara T
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
AD  - Department of Anesthesiology, Keio University School of Medicine , Tokyo , Japan.
FAU - Kobayashi, Motoi
AU  - Kobayashi M
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Woo, Jonathan D
AU  - Woo JD
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Aoyagi, Hiroko
AU  - Aoyagi H
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Marh, Karra S
AU  - Marh KS
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
FAU - Kitaoka, Hiroaki
AU  - Kitaoka H
AD  - Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University , 
      Kochi , Japan.
FAU - Matsui, Takashi
AU  - Matsui T
AD  - Center for Cardiovascular Research, Department of Anatomy, Biochemistry, and 
      Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoa , 
      Honolulu, Hawaii.
LA  - eng
GR  - G12 MD007601/MD/NIMHD NIH HHS/United States
GR  - P20 GM113134/GM/NIGMS NIH HHS/United States
GR  - P30 GM103341/GM/NIGMS NIH HHS/United States
GR  - T32 HL115505/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Webcast
DEP - 20171110
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Carbolines)
RN  - 0 (Cyclohexylamines)
RN  - 0 (Ferric Compounds)
RN  - 0 (Phenylenediamines)
RN  - 0 (Piperazines)
RN  - 0 (RSL3 compound)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (erastin)
RN  - 0 (ferrostatin-1)
RN  - 63G354M39Z (ferric citrate)
RN  - E1UOL152H7 (Iron)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H772-H775. PMID: 29212794
MH  - Animals
MH  - Carbolines/toxicity
MH  - Cell Death
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Cyclohexylamines/toxicity
MH  - Ferric Compounds/toxicity
MH  - Iron/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Myocardial Reperfusion Injury/enzymology/pathology/*prevention & control
MH  - Myocytes, Cardiac/drug effects/*enzymology/pathology
MH  - Phenylenediamines/toxicity
MH  - Piperazines/toxicity
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC5899260
OTO - NOTNLM
OT  - cardiomyocyte
OT  - ferroptosis
OT  - iron
OT  - mechanistic target of rapamycin
EDAT- 2017/11/12 06:00
MHDA- 2019/01/08 06:00
PMCR- 2019/03/01
CRDT- 2017/11/12 06:00
PHST- 2017/11/12 06:00 [pubmed]
PHST- 2019/01/08 06:00 [medline]
PHST- 2017/11/12 06:00 [entrez]
PHST- 2019/03/01 00:00 [pmc-release]
AID - ajpheart.00452.2017 [pii]
AID - H-00452-2017 [pii]
AID - 10.1152/ajpheart.00452.2017 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2018 Mar 1;314(3):H659-H668. doi: 
      10.1152/ajpheart.00452.2017. Epub 2017 Nov 10.