1,8-Cineole ameliorates endothelial injury and hypertension induced by L-NAME through regulation of autophagy via PI3K/mTOR signaling pathway

Eur J Pharmacol. 2023 Sep 5:954:175863. doi: 10.1016/j.ejphar.2023.175863. Epub 2023 Jun 26.

Abstract

Our previous data confirmed that 1,8-Cineole had an antihypertensive effect in animal models. However, it is unclear whether antihypertension is dependent on the protective effect of 1,8-Cineole on endothelial function and structure. At present, the purpose was to investigate the protective effects of 1,8-Cineole on vascular endothelial tissue in hypertensive rats and human umbilical vein endothelial cells (HUVECs). Our results showed that 1,8-Cineole significantly reduced the blood pressure and improved the vascular endothelial lesion, attenuated vascular oxidative stress and inflammation induced by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) in rats. Pretreatment with 1,8-Cineole was able to inhibit the increase in malondialdehyde (MDA) and reactive oxygen species (ROS) induced by L-NAME, and increased the release and expression of superoxide dismutase (SOD) and nitric oxide (NO). In addition, 1,8-Cineole also reversed the increase of autophagy-associated protein LC3Ⅱ/LC3Ⅰ and the decrease of P62 in vivo and in vitro respectively. There was a synergistic effect between PI3K agonists and drugs, while PI3K inhibitors blocked the efficacy of 1,8-Cineole. The addition of autophagy inhibitor chloroquine increases the expression of eNOS. Taken together, our results indicate that 1,8-Cineole has potential beneficial promising antihypertension depending on the integrity of vascular endothelial structure and function induced by L-NAME, and the mechanism involves ameliorating autophagy by regulating of PI3K/mTOR.

Keywords: 1,8-Cineole; Autophagy; Endothelial injury; Hypertension; PI3K/mTOR signaling pathway.

MeSH terms

  • Animals
  • Autophagy
  • Eucalyptol / pharmacology
  • Eucalyptol / therapeutic use
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypertension* / chemically induced
  • Hypertension* / drug therapy
  • Hypertension* / metabolism
  • NG-Nitroarginine Methyl Ester / pharmacology
  • NG-Nitroarginine Methyl Ester / therapeutic use
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • NG-Nitroarginine Methyl Ester
  • Phosphatidylinositol 3-Kinases
  • Eucalyptol
  • TOR Serine-Threonine Kinases
  • Nitric Oxide Synthase Type III
  • Nitric Oxide
  • mTOR protein, rat