Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling

Free Radic Biol Med. 2014 Apr;69:219-28. doi: 10.1016/j.freeradbiomed.2014.01.025. Epub 2014 Jan 28.

Abstract

Reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelial (RPE) cells, which is known as one major cause of age-related macular degeneration. Salvianolic acid A (Sal A) is the main effective aqueous extract of Salvia miltiorrhiza. The aim of this study was to test the potential role of Sal A against oxidative stress in cultured RPE cells and to investigate the underlying mechanistic signaling pathways. We observed that Sal A significantly inhibited hydrogen peroxide (H2O2)-induced primary and transformed RPE cell death and apoptosis. H2O2-stimulated mitogen-activated protein kinase activation, ROS production, and subsequent proapoptotic AMP-activated protein kinase activation were largely inhibited by Sal A. Further, Sal A stimulation resulted in a fast and dramatic activation of Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, followed by phosphorylation, accumulation, and nuclear translocation of the NF-E2-related factor 2 (Nrf2), along with increased expression of the antioxidant-response element-dependent gene heme oxygenase-1 (HO-1). Both Nrf2 and HO-1 were required for Sal A-mediated cytoprotective effect, as Nrf2/HO-1 inhibition abolished Sal A-induced beneficial effects against H2O2. Meanwhile, the PI3K/Akt/mTORC1 chemical inhibitors not only suppressed Sal A-induced Nrf2/HO-1 activation, but also eliminated its cytoprotective effect in RPE cells. These observations suggest that Sal A activates the Nrf2/HO-1 axis in RPE cells and protects against oxidative stress via activation of Akt/mTORC1 signaling.

Keywords: Age-related macular degeneration; Akt/mTOR; Free radicals; HO-1; Nrf2; Oxidative stress; Salvianolic acid A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caffeic Acids / administration & dosage*
  • Heme Oxygenase-1 / metabolism*
  • Lactates / administration & dosage*
  • Macular Degeneration / drug therapy*
  • Macular Degeneration / genetics
  • Macular Degeneration / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / metabolism*
  • Multiprotein Complexes / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Retinal Pigment Epithelium / drug effects*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Caffeic Acids
  • Lactates
  • Membrane Proteins
  • Multiprotein Complexes
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • salvianolic acid A
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt