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PMID:17561096

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Citation

Coatrieux, C, Sanson, M, Negre-Salvayre, A, Parini, A, Hannun, Y, Itohara, S, Salvayre, R and Auge, N (2007) MAO-A-induced mitogenic signaling is mediated by reactive oxygen species, MMP-2, and the sphingolipid pathway. Free Radic. Biol. Med. 43:80-9

Abstract

The degradation of biogenic amines by monoamine oxidase A (MAO-A) generates reactive oxygen species (ROS) which participate in serotonin and tyramine signaling. This study aimed to investigate the role of ROS in the mitogenic signaling activated during tyramine and serotonin oxidation by MAO-A in smooth muscle cells (SMC). Incubation of SMC with serotonin or tyramine induced intracellular ROS generation, and a signaling cascade involving metalloproteases and the neutral sphingomyelinase-2 (nSMase2, the initial step of the sphingolipid pathway), ERK1/2 phosphorylation, and DNA synthesis. Silencing MAO-A by siRNA, pharmacological MAO-A inhibitors (pargyline and Ro41-1049), and the antioxidant/ROS scavenger butylated hydroxytoluene (BHT) inhibited the signaling cascade, suggesting that ROS generated during tyramine oxidation by MAO-A are required. The MMP inhibitor Batimastat, MMP2-specific siRNA, and MMP2 deletion (MMP2(-/-) fibroblasts) blocked nSMase activation and SMC proliferation, suggesting a role for MMP2 in this signaling pathway. Silencing nSMase2 by siRNA did not inhibit ROS generation and MMP2 activation, but blocked SMC proliferation induced by tyramine, suggesting that nSMase2 is downstream MMP2. These findings demonstrate that H(2)O(2)-generated during tyramine oxidation by MAO-A triggers a stress-induced mitogenic signaling via the MMP2/sphingolipid pathway, which could participate in excessive remodeling and alteration of the vascular wall.

Links

PubMed Online version:10.1016/j.freeradbiomed.2007.03.036

Keywords

Animals; Biogenic Amines/metabolism; Biogenic Amines/pharmacology; Blood Vessels/metabolism; Butylated Hydroxytoluene/pharmacology; Cell Proliferation; Free Radical Scavengers/pharmacology; Hydrogen Peroxide/metabolism; Matrix Metalloproteinase 2/genetics; Matrix Metalloproteinase 2/metabolism; Matrix Metalloproteinase Inhibitors; Mice; Mice, Mutant Strains; Mitogens/metabolism; Mitogens/pharmacology; Monoamine Oxidase/drug effects; Monoamine Oxidase/genetics; Monoamine Oxidase/metabolism; Monoamine Oxidase Inhibitors/pharmacology; Myocytes, Smooth Muscle/cytology; Myocytes, Smooth Muscle/drug effects; Myocytes, Smooth Muscle/enzymology; Oxidation-Reduction; Pargyline/pharmacology; Phenylalanine/analogs & derivatives; Phenylalanine/pharmacology; RNA, Small Interfering/pharmacology; Rabbits; Reactive Oxygen Species/metabolism; Serotonin/metabolism; Serotonin/pharmacology; Signal Transduction; Sphingolipids/metabolism; Thiazoles/pharmacology; Thiophenes/pharmacology; Tyramine/metabolism; Tyramine/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NSMA2

acts_upstream_of_or_within

GO:0048661: positive regulation of smooth muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NSMA2

acts_upstream_of_or_within

GO:0007165: signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NSMA2

acts_upstream_of_or_within

GO:0034614: cellular response to reactive oxygen species

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AOFA

acts_upstream_of_or_within

GO:0009967: positive regulation of signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MMP2

acts_upstream_of_or_within

GO:0034614: cellular response to reactive oxygen species

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MMP2

acts_upstream_of_or_within

GO:0048661: positive regulation of smooth muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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