Endoplasmic reticulum stress-induced iRhom2 up-regulation promotes macrophage-regulated cardiac inflammation and lipid deposition in high fat diet (HFD)-challenged mice: Intervention of fisetin and metformin

Free Radic Biol Med. 2019 Sep:141:67-83. doi: 10.1016/j.freeradbiomed.2019.05.031. Epub 2019 May 30.


Endoplasmic reticulum stress (ERS) has been implicated in obesity-associated cardiac remodeling and dysfunction. Inactive rhomboid protein 2 (iRhom2), also known as Rhbdf2, is an inactive member of the rhomboid intramembrane proteinase family, playing an essential role in regulating inflammation. Nevertheless, the role of ERS-meditated iRhom2 pathway in metabolic stress-induced cardiomyopathy remains unknown. In the study, we showed that 4-PBA, as an essential ERS inhibitor, significantly alleviated high fat diet (HFD)-induced metabolic disorder and cardiac dysfunction in mice. Additionally, lipid deposition in heart tissues was prevented by 4-PBA in HFD-challenged mice. Moreover, 4-PBA blunted the expression of iRhom2, TACE, TNFR2 and phosphorylated NF-κB to prevent HFD-induced expression of inflammatory factors. Further, 4-PBA restrained HFD-triggered oxidative stress by promoting Nrf-2 signaling. Importantly, 4-PBA markedly suppressed cardiac ERS in HFD mice. The anti-inflammation, anti-ERS and anti-oxidant effects of 4-PBA were verified in palmitate (PAL)-incubated macrophages and cardiomyocytes. In addition, promoting ERS could obviously enhance iRhom2 signaling in vitro. Intriguingly, our data demonstrated that PAL-induced iRhom2 up-regulation apparently promoted macrophage to generate inflammatory factors that could promote cardiomyocyte inflammation and lipid accumulation. Finally, interventions by adding fisetin or metformin significantly abrogated metabolic stress-induced cardiomyopathy through the mechanisms mentioned above. In conclusion, this study provided a novel mechanism for metabolic stress-induced cardiomyopathy pathogenesis. Therapeutic strategy to restrain ROS/ERS/iRhom2 signaling pathway could be developed to prevent myocardial inflammation and lipid deposition, consequently alleviating obesity-induced cardiomyopathy.

Keywords: Cardiomyopathy; Inflammation; Lipid deposition; Obesity; ROS/ERS/iRhom2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Carrier Proteins / metabolism*
  • Diet, High-Fat
  • Echocardiography
  • Endoplasmic Reticulum Stress*
  • Flavonoids / pharmacology*
  • Flavonols
  • Gene Expression Regulation
  • Heart / drug effects
  • Heart / physiopathology*
  • Inflammation
  • Lipid Metabolism*
  • Macrophages / metabolism
  • Male
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / pathology
  • Oxidative Stress
  • Palmitates / metabolism
  • Signal Transduction
  • Up-Regulation


  • Carrier Proteins
  • Flavonoids
  • Flavonols
  • Palmitates
  • iRhom2 protein, mouse
  • Metformin
  • fisetin