Naringenin ameliorates homocysteine induced endothelial damage via the AMPKα/Sirt1 pathway

J Adv Res. 2021 Jan 23;34:137-147. doi: 10.1016/j.jare.2021.01.009. eCollection 2021 Dec.

Abstract

Introduction: Endothelial damage (ED) has been implicated in accelerating the development of atherosclerosis. The latter condition is a risk factor for developing several cardiovascular diseases (CVDs) associated with high morbidity and mortality rates worldwide.

Objectives: In our previous studies, we found naringenin (Nar), a bioactive flavanone compound, to protect against mitochondrial damage and oxidative stress. Though the pleiotropic effects of Nar have been well described, precise cytoprotective mechanisms of Nar against homocysteine (Hcy) induced ED remains elusive. Understanding these events may give an insight in to prevention and treatment of CVDs.

Methods: After ruling out the NMDA-R1 mediated pathway, RNA-Seq, a novel transcriptomic technique uncovered AMPK signaling pathway was identified as the mechanism with which Nar corrects ED. Further in vivo and in vitro tests validated the role of Nar against ED.

Results: In particular, Nar activates AMPKα/Sirt1 signaling pathway, which restores mitochondrial Ca2+ balance and ultimately lowered production of reactive oxygen species (ROS). Activated AMPKα/Sirt1 signaling pathway also up-regulates endothelial nitric oxide synthase (eNOS) activity, and then increasing the production of nitric oxide (NO), ultimately ameliorating ED.

Conclusion: Nar could increase the ROS elimination and decrease eNOS uncoupling, subsequently upregulate the NO bioavailability and endothelial function by activating AMPKα/Sirt1 signaling pathway.

Keywords: AMPKα/Sirt1 signaling pathway; Endothelial damage; Naringenin; RNA-Seq; eNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • Flavanones* / pharmacology
  • Homocysteine
  • Sirtuin 1* / genetics

Substances

  • Flavanones
  • Homocysteine
  • AMP-Activated Protein Kinases
  • Sirtuin 1
  • naringenin