Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress

Hiroki Kitakata, Jin Endo, Shun Hashimoto, Erika Mizuno, Hidenori Moriyama, Kohsuke Shirakawa, Shinichi Goto, Yoshinori Katsumata, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 1α–X-box binding protein 1 (IRE1α-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.

Original languageEnglish
Pages (from-to)185-190
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume572
DOIs
Publication statusPublished - 2021 Oct 1

Keywords

  • Diastolic dysfunction
  • Heart failure with preserved ejection fraction
  • Imeglimin
  • Unfolded protein response

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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