PMID- 34375928
OWN - NLM
STAT- MEDLINE
DCOM- 20211117
LR  - 20211117
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 572
DP  - 2021 Oct 1
TI  - Imeglimin prevents heart failure with preserved ejection fraction by recovering 
      the impaired unfolded protein response in mice subjected to cardiometabolic 
      stress.
PG  - 185-190
LID - S0006-291X(21)01127-X [pii]
LID - 10.1016/j.bbrc.2021.07.090 [doi]
AB  - The pathogenesis of heart failure with preserved ejection fraction (HFpEF) in 
      obese diabetic patients has been implicated in metainflammation. Increased 
      expression of inducible nitric oxide synthase (iNOS) and dysfunction of the 
      unfolded protein response (UPR), especially inositol-requiring enzyme 1alpha-X-box 
      binding protein 1 (IRE1alpha-Xbp1s) signaling in the heart, have been associated with 
      HFpEF. We investigated the effect of imeglimin, a potential new treatment for 
      type 2 diabetes, on the pathogenesis of HFpEF. We induced obesity, impaired 
      glucose tolerance, and cardiac hypertrophy with fibrosis, fat accumulation, and 
      diastolic dysfunction in wild-type mice with a high-fat diet (HFD) and the nitric 
      oxide synthase (NOS) inhibitor l-NAME for 16 weeks. Treatment with imeglimin 
      starting at 10 weeks not only improved their abnormal systemic glucose metabolism 
      and visceral obesity but also their cardiac abnormalities. We found that 
      imeglimin suppressed the upregulation of iNOS, and restored the expression of 
      Xbp1s and the expression of the E3 ubiquitin ligase STIP1 homology and 
      U-box-containing protein 1 (STUB1), which is responsible for the degradation of 
      Forkhead box protein O1 (FoxO1), a direct transcriptional target of Xbp1s. It 
      also suppressed the excessive transcriptional activity of FoxO1, which is located 
      downstream of Xbp1s and is involved in the form development of HFpEF and cardiac 
      adipogenesis. Imeglimin also restored the expression of Glutathione peroxidase 4 
      (GPX4), which protects cells against excess lipid peroxidation and governs a 
      novel form of programmed cell death, called ferroptosis.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Kitakata, Hiroki
AU  - Kitakata H
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: kitkat@keio.jp.
FAU - Endo, Jin
AU  - Endo J
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: jinendo@keio.jp.
FAU - Hashimoto, Shun
AU  - Hashimoto S
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: hashi8moto3@gmail.com.
FAU - Mizuno, Erika
AU  - Mizuno E
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: mizunoerika74@keio.jp.
FAU - Moriyama, Hidenori
AU  - Moriyama H
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: h.moriyama@keio.jp.
FAU - Shirakawa, Kohsuke
AU  - Shirakawa K
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: shirakawa19840905@gmail.com.
FAU - Goto, Shinichi
AU  - Goto S
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: shinichi.and@gmail.com.
FAU - Katsumata, Yoshinori
AU  - Katsumata Y
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: goodcentury21@gmail.com.
FAU - Fukuda, Keiichi
AU  - Fukuda K
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: kfukuda@a2.keio.jp.
FAU - Sano, Motoaki
AU  - Sano M
AD  - Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. 
      Electronic address: msano@a8.keio.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210730
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Triazines)
RN  - UU226QGU97 (imeglimin)
SB  - IM
MH  - Animals
MH  - Heart Failure/metabolism/*prevention & control
MH  - Mice
MH  - Oxidative Stress/drug effects
MH  - Protein Unfolding
MH  - Stroke Volume/*drug effects
MH  - Triazines/*pharmacology
OTO - NOTNLM
OT  - Diastolic dysfunction
OT  - Heart failure with preserved ejection fraction
OT  - Imeglimin
OT  - Unfolded protein response
COIS- Declaration of competing interest Dainippon Sumitomo Pharma Co., Ltd. and Poxel 
      Co., Ltd. provided the imeglimin.
EDAT- 2021/08/11 06:00
MHDA- 2021/11/18 06:00
CRDT- 2021/08/10 20:23
PHST- 2021/07/07 00:00 [received]
PHST- 2021/07/26 00:00 [revised]
PHST- 2021/07/26 00:00 [accepted]
PHST- 2021/08/11 06:00 [pubmed]
PHST- 2021/11/18 06:00 [medline]
PHST- 2021/08/10 20:23 [entrez]
AID - S0006-291X(21)01127-X [pii]
AID - 10.1016/j.bbrc.2021.07.090 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2021 Oct 1;572:185-190. doi: 
      10.1016/j.bbrc.2021.07.090. Epub 2021 Jul 30.