The Pulmonary Hypertensive Fawn-hooded Rat Has a Normal Serotonin Transporter Coding Sequence (original) (raw)
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Serotonin Signaling in Pulmonary Hypertension
Circulation Research, 2006
Mark de Caestecker S erotonin (5-HT, 5-hydroxytryptamine) has long been recognized as one of the most potent naturally occurring pulmonary vasoconstrictors. 1 It was first implicated in the pathogenesis of pulmonary arterial hypertension (PAH) after an outbreak of the disease in Switzerland in the 1960's among patients taking aminorex fumarate, an appetite suppressant that inhibits serotonin uptake by platelets. 2 Since that time further outbreaks of PAH have been identified in Europe and the USA associated with the use of fenfluraminederivate anorexigens, 3-5 eventually leading to their withdrawal from the world market in 1997. Although this was, at least in retrospect, a predictable tragedy, it has ironically opened avenues of research into the biology of serotonin signaling in PAH. As fenfluramine-derivatives are substrates for the serotonin transporter (5-HTT, SERT) proteins, 6 this suggests that abnormal SERT expression or functional activity could play a role in the pathogenesis of PAH. There is now a body of evidence supporting this hypothesis that provides hope for the development of effective therapeutic strategies targeting specific components of this signaling pathway in patients with these diseases. Most of the serotonin produced in the body is secreted by enterochromaffin cells of the intestine into the portal circulation where it is partially metabolized by the liver. However, levels of free circulating serotonin are maintained in the low nanomolar range through energy-dependent SERT-mediated transport into platelets. This led some researchers to hypothesize that fenfluramines might cause PAH by increasing free plasma levels of serotonin. However, this hypothesis is inconsistent with the observation that chronic treatment with fenfluramine-derivatives if anything reduces plasma levels of serotonin. 6 This suggests that other SERT-related effects promote PAH in susceptible patients. This is supported by the observation that patients with idiopathic PAH have increased frequency of the so called L-type polymorphism in the SERT promotor, which is associated with increased SERT expression and activity in platelets and pulmonary artery smooth muscle cells (PASMCs). 7 These studies have recently come under fire as more extensive analyses have failed to confirm an association between the L-genotype and idiopathic or familial PAH. 8,9 Nonetheless, subgroup analysis suggests that the homozygous LL-SERT genotype is associated with early The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
High Plasma Serotonin Levels in Primary Pulmonary Hypertension
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
Elevated plasma serotonin is associated with primary pulmonary hypertension (PPH). To test whether this elevation could be related to platelet activation, the 2 pools of blood serotonin (platelets and plasma) and plasma 5-hydroxyindoleacetic acid (5-HIAA) as well as markers of platelet activation (␣ IIb  3 , CD36, P-selectin, and CD63 membrane epitopes) were measured in 16 patients with severe PPH (group 1) before and at days 10 and 40 of treatment with a continuous infusion of epoprostenol (prostacyclin). The same biological parameters were also measured in 19 healthy subjects (group 2) and in 10 patients after cardiovascular surgery with extracorporeal circulation (group 3), a condition known to profoundly activate the platelets. Twelve PPH patients showed hemodynamic and clinical improvement, 3 remained stable, and 1 had the treatment stopped because of clinical aggravation. At day 0, mean plasma serotonin (5-hydroxytryptamine [5-HT]) concentration was much higher in PPH patients than in normal subjects (34.4Ϯ21.2 versus 9.1Ϯ6.0 nmol/L, respectively; PϽ0.001) and positively correlated with total pulmonary resistance. The mean platelet 5-HT content was not significantly different in PPH compared with normal individuals. Mean plasma 5-HIAA concentrations were much higher in PPH than in normal patients (162Ϯ57 versus 61Ϯ7 nmol/L, respectively; PϽ0.001). These parameters did not significantly change during epoprostenol treatment. There was no correlation between the changes in plasma 5-HT during treatment and clinical or hemodynamic improvement. In PPH patients, the mean platelet volume significantly decreased (ANOVA, PϽ0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of ␣ IIb  3 and CD36 epitopes. When compared with control platelets, the number of ␣ IIb  3 epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300Ϯ7140 for PPH patients versus 36 010Ϯ3930 for control subjects, Pϭ0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590Ϯ5080 for PPH patients versus 11 900Ϯ1790 for control subjects), decreased during treatment (ANOVA, Pϭ0.038) and became significantly low at day 40 (8660Ϯ3520, PϽ0.001). The number of CD63 epitopes was not elevated, and P-selectin was never detected at any time point on PPH platelets. This glycoprotein profile indicates that the platelets of PPH patients were not highly activated but had an accelerated turnover and returned to normal under epoprostenol treatment without change of the elevated plasma serotonin, characteristic of PPH. In conclusion, neither platelet activation nor a significant alteration of the 5-HT endothelial metabolism explains the high level of plasma 5-HT in PPH patients. The 5-HT plasma concentration is not a predictive marker of the severity of PPH, and its evolution is independent of the clinical and hemodynamic status. Treatment by a potent antiaggregating agent, epoprostenol, does not affect the increase of plasma 5-HT, despite a therapeutic benefit.
Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin
AJP: Lung Cellular and Molecular Physiology, 2007
HMG-CoA-reductase inhibitors (statins) influence lipid metabolism and have pleiotropic effects. Several statins reduce various forms of pulmonary hypertension (PH) in animal models. The relationship between atorvastatin and expression of serotonin transporter protein (5-HTT) remains unknown. This study focused on the effects of atorvastatin on the course of monocrotaline (MCT)-induced PH and its relation to 5-HTT expression. Male Sprague-Dawley rats were challenged with MCT with or without subsequent daily oral treatment with 0.1, 1, and 10 mg/kg of atorvastatin for 28 days. Over the 4-wk course, the progression of PH was followed by transthoracic echocardiography [pulmonary artery pressure was assessed by pulmonary artery flow acceleration time (PAAT), an estimate reciprocal to pulmonary artery pressure], and, at the end of the 4-wk course, invasive right ventricular pressure, right ventricular weight, quantitative morphology, and 5-HTT expression were measured. MCT caused signific...
Neurochemistry International, 1998
Neurochem[ Int[ 22 "0888# 408Ð412 9086!9075:88:, ! see front matter Þ 0888 Elsevier Science Ltd[ All rights reserved[ PII] S 9 0 8 6 ! 9 0 7 5 " 8 7 # 9 9 9 4 8 ! X Serotonin transporter on rat platelets] levels of mRNA underlie inherited di}erences in uptake kinetics B[ Jernej \ D[ Hranilovic \ L[ C ic ³in!S ain Laboratory of Neurochemistry and Molecular Neurobiolo`y\ Ru`jer Bos ³kovic Institute\ Bijenic ³ka 43 and Croatian Institute for Brain Research\ S alata 01^HR!09 999 Za`reb\ Croatia
Platelet serotonin content and uptake in spontaneously hypertensive rats
Life Sciences, 1985
Platelet serotonin (5-HT) content and uptake were studied in male SHR and WKY at various ages. Blood was withdrawn from the carotid artery under anesthesia and 5-HT levels determined from platelet rich plasma (PRP) using a HPLC technique coupled with an electrochemical detection method. Platelet 5-HT uptake was studied by incubating PRP at 37°C for 10 sec ~ith increasing concentrations of 3H-5HT. Lineweaver-Burk plots of 3H-5HT uptake were linear suggesting simple Michaelis-Menten uptake kinetics.
Serotonin transporter kinetics in rats selected for extreme values of platelet serotonin level
Life Sciences, 2005
By selective breeding of Wistar rats for the extreme values of platelet serotonin (5HT) level (PSL), we have developed earlier two sublines of animals differing markedly in this parameter. Further studies, performed on the protein and mRNA levels, revealed platelet serotonin transporter (5HTt) as parameter underlying mentioned differences in PSL between sublines. In this work, we have performed full-kinetic analysis of platelet serotonin uptake (PSU) in animals from the genetically selected sublines. The results demonstrated marked differences in maximal velocity (V max ) of the 5HT transporter, as contrasted to the lack of any difference in the Michaelis constant (K m ). High correlation between PSL and V max of PSU was demonstrated, revealing that the number of membrane 5HT transporter sites is under genetic control and responsible for marked differences in PSL between high-and low-5HT sublines. These results enabled further selective breeeding of animals for the extremes of V max of platelet 5HT transporter, and so the development of more specific model bWistar-Zagreb 5HT ratsQ. D
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
2009
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs
Physiological characteristics of serotonin transporters on rat platelets
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 1998
Physiological characteristics of serotonin (5-hydroxytryptamine, 5HT) transport through the platelet membrane was investigated in Wistar rats with our recently developed method permitting repetitive measurements of transporter kinetics in individual animals. Full kinetic analysis in the population of 91 animals revealed Michaelis constant (K m) of 0.158 90.025 vM and maximal velocity (V max) of 5HT uptake of 225932 pmol per 10 8 platelets min − 1 (mean9 S.D.). Both kinetic parameters demonstrated normal distribution curves, which for V max were slightly skewed toward higher than average values. No gender effect was shown in frequency distributions, mean values and variability of kinetic parameters. A significant intraindividual correlation between kinetic parameters was found suggesting compensation at the level of the plasma membrane. Kinetic parameters were not influenced by age (until the middle age) or annual cycle (under laboratory conditions) and were shown to be fairly stable in time, supporting the view that platelet 5HT transport kinetics could be a useful biological trait marker.