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MAO-A-induced mitogenic signaling is mediated by reactive oxygen species, MMP-2, and the sphingolipid pathway

Christelle Coatrieux1, Marie Sanson, Anne Negre-Salvayre

  • 1INSERM UMR-466, Department of Biochemistry, IFR-31, CHU Rangueil, avenue Jean Poulhes, TSA-50032, 31059 Toulouse Cedex 9, France.

Free Radical Biology & Medicine
|June 15, 2007
PubMed

Insights

Monoamine oxidase A (MAO-A) generates reactive oxygen species (ROS) during biogenic amine degradation. This study reveals ROS trigger smooth muscle cell proliferation via a metalloprotease and sphingolipid pathway, potentially impacting vascular remodeling.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Vascular Biology

Background:

  • Biogenic amines like serotonin and tyramine are degraded by monoamine oxidase A (MAO-A).
  • This degradation process generates reactive oxygen species (ROS), which are implicated in cellular signaling pathways.
  • The specific role of ROS in MAO-A-mediated signaling in smooth muscle cells (SMC) requires further elucidation.

Purpose of the Study:

  • To investigate the role of ROS in the mitogenic signaling cascade activated by tyramine and serotonin oxidation by MAO-A in SMC.
  • To identify the key molecular players involved in this ROS-dependent signaling pathway.

Main Methods:

  • Smooth muscle cells (SMC) were incubated with serotonin or tyramine.
  • MAO-A was inhibited using siRNA or pharmacological inhibitors (pargyline, Ro41-1049).
  • ROS generation was assessed, and signaling components including metalloproteases (MMP2), neutral sphingomyelinase-2 (nSMase2), ERK1/2 phosphorylation, and DNA synthesis were analyzed. Antioxidants like butylated hydroxytoluene (BHT) were used.

Main Results:

  • Serotonin and tyramine induced intracellular ROS generation and a signaling cascade involving metalloproteases, nSMase2, ERK1/2 phosphorylation, and DNA synthesis in SMC.
  • Inhibition of MAO-A, ROS scavenging, or blocking MMP2 (via inhibitor, siRNA, or genetic deletion) abrogated this signaling cascade and SMC proliferation.
  • nSMase2 acts downstream of MMP2, as its silencing inhibited proliferation but not ROS or MMP2 activation.

Conclusions:

  • Hydrogen peroxide (H2O2) generated during tyramine oxidation by MAO-A initiates a stress-induced mitogenic signaling pathway.
  • This pathway involves MMP2 and the sphingolipid pathway, leading to SMC proliferation.
  • This mechanism may contribute to excessive vascular wall remodeling and alterations.

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