Soluble epoxide hydrolase deletion attenuated nicotine-induced arterial stiffness via limiting the loss of SIRT1

Am J Physiol Heart Circ Physiol. 2021 Aug 1;321(2):H353-H368. doi: 10.1152/ajpheart.00979.2020. Epub 2021 Jun 18.


Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice (Ephx2-/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.

Keywords: SIRT1; arterial stiffness; nicotine; soluble epoxide hydrolase; vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / pharmacology
  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / physiopathology
  • Epoxide Hydrolases / genetics*
  • Matrix Metalloproteinase 2 / drug effects
  • Matrix Metalloproteinase 2 / genetics
  • Mice
  • Mice, Knockout
  • Niacinamide / pharmacology*
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / drug effects
  • Sirtuin 1 / metabolism*
  • Vascular Stiffness / drug effects*
  • Vascular Stiffness / genetics
  • Vasodilator Agents / pharmacology
  • Vitamin B Complex / pharmacology*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Nicotinic Agonists
  • Vasodilator Agents
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Vitamin B Complex
  • Niacinamide
  • 11,12-epoxy-5,8,14-eicosatrienoic acid
  • Nicotine
  • Epoxide Hydrolases
  • Ephx2 protein, mouse
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • 8,11,14-Eicosatrienoic Acid

Associated data

  • figshare/10.6084/m9.figshare.14566491.v2