Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves.
Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2*.-) was measured in heart valves from explanted human hearts that were not used for transplantation. (O2*.-) levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in (O2*.-). Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased (O2*.-) levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in (O2*.-) during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated (O2*.-), and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.
Peña-Silva
Ricardo A
RA
Departments of Pharmacology, University of Iowa Carver College of Medicine, Iowa City School of Medicine, Iowa City, Iowa 52242, USA. ricardo-pena@uiowa.edu
Miller
Jordan D
JD
Chu
Yi
Y
Heistad
Donald D
DD
D000975:Antioxidants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006351:Heart Valves / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D000975:Antioxidants; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; D013481:Superoxides; D012701:Serotonin; D008995:Monoamine Oxidase; D004298:Dopamine