MAO-A-induced mitogenic signaling is mediated by reactive oxygen species, MMP-2, and the sphingolipid pathway.
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.
Coatrieux
Christelle
C
INSERM UMR-466, Department of Biochemistry, IFR-31, CHU Rangueil, avenue Jean Poulhes, TSA-50032, 31059 Toulouse Cedex 9, France.
Sanson
Marie
M
Negre-Salvayre
Anne
A
Parini
Angelo
A
Hannun
Yusuf
Y
Itohara
Shigeyoshi
S
Salvayre
Robert
R
Auge
Nathalie
N
D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism* / Q000494:pharmacology; D001808:Blood Vessels / Q000378:metabolism; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D049109:Cell Proliferation; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008817:Mice, Mutant Strains; D008934:Mitogens / Q000378:metabolism* / Q000494:pharmacology; D008995:Monoamine Oxidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010293:Pargyline / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014439:Tyramine / Q000378:metabolism / Q000494:pharmacology
D001679:Biogenic Amines; D016166:Free Radical Scavengers; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens; D008996:Monoamine Oxidase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013107:Sphingolipids; D013844:Thiazoles; D013876:Thiophenes; D002084:Butylated Hydroxytoluene; D012701:Serotonin; C063456:Ro 41-1049; D010649:Phenylalanine; D010293:Pargyline; D006861:Hydrogen Peroxide; C080985:batimastat; D008995:Monoamine Oxidase; D020778:Matrix Metalloproteinase 2; D014439:Tyramine