TY - JOUR
T1 - Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves
AU - Peña-Silva, Ricardo A.
AU - Miller, Jordan D.
AU - Chu, Yi
AU - Heistad, Donald D.
PY - 2009/10
Y1 - 2009/10
N2 - 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. O 2.- 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.
AB - 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. O 2.- 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.
KW - Carcinoid syndrome
KW - Reactive oxygen species
KW - Serotonin
KW - Superoxide
KW - Valvulopathy
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U2 - 10.1152/ajpheart.00570.2009
DO - 10.1152/ajpheart.00570.2009
M3 - Article
C2 - 19666839
AN - SCOPUS:70349617848
SN - 0363-6135
VL - 297
SP - H1354-H1360
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 4
ER -