Abstract
Biogenic amines have been demonstrated to protect cells from apoptotic cell death. Herein we show for the first time that serotonin and dopamine increase H2S production by the endogenous enzyme cystathionine-β-synthase (CBS) and protect cells against hypothermia/rewarming induced reactive oxygen species (ROS) formation and apoptosis. Treatment with both compounds doubled CBS expression through mammalian target of rapamycin (mTOR) and increased H2S production in cultured rat smooth muscle cells. In addition, serotonin and dopamine treatment significantly reduced ROS formation. The beneficial effect of both compounds was minimized by inhibition of their re-uptake and by pharmacological inhibition of CBS or its down-regulation by siRNA. Exogenous administration of H2S and activation of CBS by Prydoxal 5′-phosphate also protected cells from hypothermic damage. Finally, serotonin and dopamine pretreatment of rat lung, kidney, liver and heart prior to 24 h of hypothermia at 3°C followed by 30 min of rewarming at 37°C upregulated the expression of CBS, strongly reduced caspase activity and maintained the physiological pH compared to untreated tissues. Thus, dopamine and serotonin protect cells against hypothermia/rewarming induced damage by increasing H2S production mediated through CBS. Our data identify a novel molecular link between biogenic amines and the H2S pathway, which may profoundly affect our understanding of the biological effects of monoamine neurotransmitters.
Highlights
Ischemia is a condition suffered by cells in tissues when deprived of blood flow due to inadequate nutrient and oxygen supplementation
Our data show that the cellular uptake of serotonin and dopamine prevents hypothermia/ rewarming induced cell apoptosis by H2S formation through CBS upregulation and probably allosteric activation
Both compounds attenuate the increase in reactive oxygen species (ROS) formation in cells subjected to hypothermia/rewarming
Summary
Ischemia is a condition suffered by cells in tissues when deprived of blood flow due to inadequate nutrient and oxygen supplementation. The restoration of blood flow following an ischemic condition causes reperfusion damage [1] mainly due to the rapid generation of ROS from the start of reperfusion [2] and characterized by apoptotic cell death [3]. Many mammalian cell types are vulnerable to prolonged and profound hypothermic storage mainly due to the burst of reactive oxygen species (ROS). The apoptotic damage brought about by either ischemia or hypothermia results from a burst in ROS formation during reperfusion or rewarming. Several observations suggest that catecholamines protect from cell death after hypothermia and the subsequent rewarming. In initial experiments in search of mechanisms conveying a natural resistance to hypothermia on cells of a hibernating species, the Syrian hamster, we found that their ductus deferens (DDT-1 MF2)
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