35 research outputs found
0122: The serotonergic system in pathological human cardiac valves. What is the role of progenitors cells expressing the 5-HT2B receptor?
Many compounds (pergolide, cabergoline, fenfluramine, ectasy) were described as inducers of fibrotic valvular lesions, a rare but severe drug reaction. All these drugs share in common the pharmacological property to activate a serotonergic receptor subtype, the 5HT2B. Together with the well known âcarcinoid heartâ that is a valvulopathy due to high amounts of circulating serotonin, these observations lead to the hypothesis that cardiac valves express a âserotonergic systemâ that could be activated by 5-HT or 5-HTR agonists. The aim of this work was to characterize the pattern of expression of 5-HT2A,2B,4 receptors, the serotonin transporter (SERT) and the biosynthesis peripheral enzyme (Tph1) in various valvulopathies. Thirty degenerated human valves were collected: 11 calcified aortic valves (CAV), 5 sclerotic aortic valves (SAV), 11 dystrophic mitral valves (DMV). They were analyzed by RT-qPCR and immunohistochemistery. All samples express 5HT2A,2B,4 receptors, SERT and Tph1. In these valve tissues, the amount of 5HT2B receptor (5HT2B R) mRNA is higher than the 5HT2A one (5HT2A R) : Î Ct (5HT2B R -18S) = 12,53±1,12 vs Î Ct (5HT2A R -18S) = 15,95±2,37 for CAV, Î Ct (5HT2B R -18S) = 13,04±2,62 vs Î Ct (5HT2A R - 18S)=16,00±1,46 for SAV, Î Ct (5HT2B R -18S) = 12,34±0,77 vs Î Ct (5HT2A R -18S) = 16,14±0,86 for DMV. The amounts of SERT, Tph1 and 5HT4 receptor mRNA are negligible whatever valve and etiology. At a topographical point of view, 5HT2BR expression is found in endothelial cells (at the valve surface) but also inside valve lesions, by interstitial cells (smooth muscle α-actin and vimentin positive cells) located in an abundant glycosaminoglycan matrix. Characterization of these cells is in progress. In particular, we characterize the high amount CD34+ hematopoietic progenitors that are highly present in fibromyxoid lesions. To summarize, 5HT2A,2B,4 receptors, SERT and Tph1 are expressed in aortic and mitral diseased valves. The amounts of 5HT2A,2B R mRNA are equal between mitral and aortic valves. The contribution of the two 5-HT2 receptors in valve degeneration is now under investigation whatever the pathological process considered
How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains
Background Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies. Methods The present work was designed in an attempt to determine guidelines in the field of saltinduced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry). Results In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges. Conclusions Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites
Involvement of serotonin and 5-HT2A/2B receptors in cardiac valve and bioprosthetic remodeling
LâhypothĂšse dâun lien entre valvulopathies et surexpression du systĂšme sĂ©rotoninergique fait suite aux lĂ©sions valvulaires observĂ©es lors de tumeurs carcinoĂŻdes (taux sanguins de 5-HT Ă©levĂ©s) et lors de lâutilisation chronique dâagonistes sĂ©rotoninergiques 5-HT2 (comme les dĂ©rivĂ©s de lâergot de seigle, les fenfluramines). Le dogme actuel repose sur un effet prolifĂ©ratif de la sĂ©rotonine, activant des cellules rĂ©sidentes valvulaires, mais ne suffit pas Ă expliquer la dĂ©gĂ©nĂ©rescence de bioprothĂšses acellulaires. Nos travaux ont permis dâidentifier des cellules progĂ©nitrices endothĂ©liales (CD34+/CD309+), exprimant les rĂ©cepteurs 5-HT2A et 5-HT2B, au sein de lĂ©sions valvulaires humaines aortiques et mitrales, quelle que soit lâĂ©tiologie de leur dĂ©gĂ©nĂ©rescence. Ils ont permis de mettre en Ă©vidence un rĂŽle double de la sĂ©rotonine dans la dĂ©gĂ©nĂ©rescence valvulaire : 1) la stimulation des rĂ©cepteurs 5-HT2B contribue Ă la mobilisation sanguine des progĂ©niteurs CD34+ (recrutĂ©s Ă partir de la moelle osseuse, et migrant dans le tissu valvulaire), 2) le rĂŽle des rĂ©cepteurs 5-HT2 dans la transdiffĂ©renciation des progĂ©niteurs endothĂ©liaux en cellules activĂ©es, au sein de la matrice valvulaire. La suite de ce travail permettra de dĂ©velopper 1) un biomarqueur prĂ©dictif dâatteinte valvulaire, dans des populations Ă haut risque, 2) de dĂ©velopper un modĂšle cellulaire de valvulopathie pour Ă©tudier les mĂ©canismes impliquĂ©s dans le remodelage valvulaire et leurs voies de signalisation, et 3) de dĂ©terminer des cibles thĂ©rapeutiques autour du systĂšme sĂ©rotoninergique, permettant de ralentir la progression des lĂ©sions et retarder lâexĂ©rĂšse chirurgicale, seule alternative actuelle.AbstractSeveral studies have established an association between some cardiac valve injuries and overexpression of the serotonergic system. Valve lesions are observed following carcinoid tumours (with high blood levels of 5-HT) and during the chronic use of 5-HT2 serotonergic agonists (ergot derivatives or fenfluramines). The current dogma is based on a mitogenic effect of serotonin, by activating 5-HT2B receptors, leading to resident valvular cells proliferation, but does not explain the degeneration of acellular cardiac bioprosthesis. Our work identified endothelial progenitor cells (CD34 + / CD309 +), expressing 5-HT2A and 5-HT2B receptors, in human aortic and mitral valve lesions, regardless of the etiology of their degeneration. Our work highlights the dual role of serotonin in valvular degeneration: 1) stimulation of the 5-HT2B receptor contributes to blood mobilization of CD34+ progenitors (recruited from the bone marrow, and migrating in the valve tissue), 2) the role of 5-HT2 receptors in the transdifferentiation of endothelial progenitor cells in activated valvular cells. The results of this work could drive to the development of 1) a predictive biomarker of cardiac valve injuries in high-risk populations, 2) a model to study heart valve disease cellular and molecular mechanisms, and 3) identify therapeutic targets around the serotonergic system, to slower the progression of the lesions and delay surgical replacement, the only current alternative
Cardiovascular remodeling and the peripheral serotonergic system
International audiencePlasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system
Targeting myocardial reperfusion injuries with cyclosporine in the CIRCUS Trial - Pharmacological reasons for failure
The mitochondrial permeability transition (mPTP) is a key feature of cardiac cell death in ischemia-reperfusion injury (I/R). The mPTP blocker, cyclosporine A (CsA), has been shown to give protection against reperfusion-induced myocardial necrosis and troubles generated by acute coronary artery repermeabilization. Nevertheless, the results of the CIRCUS trial (Does Cyclosporine Improve Clinical Outcome in ST-Elevation Myocardial Infarction Patients) seem to go against this hypothesis. Pharmacological reasons linked to CsA pharmacokinetics and pharmacodynamics could be suggested. First, it could be explained by a limited diffusion of the drug in the area at risk, due to the only inclusion of patients with a TIMI 0 or 1 coronary blood flow in the anterior territory and the absence of collateral perfusion. Second, to explain a low tissue diffusion of the compound, blood cell capture and high metabolism could be suggested. Moreover, CsA is highly metabolized by cytochrome P450 3A4 (CYP3A4), a polymorphic enzyme leading to variations of Cmax and AUC between 10-20% in patients using CsA. Finally, CsA blocks calcineurin, a protein implied in I/R damage but calcineurin inhibition could contribute to protection towards I/R damage only when Rcan1, a calcineurin natural inhibitor, expression is low. The results of the CIRCUS trial are disappointing and could contribute to the withdrawal of the mPTP blockade pharmacological strategy as a way to protect the myocardium from I/R lesions. Nevertheless, many pharmacological insights could have contributed to an increased variability and, as a consequence, an important reduction of the pharmacological power of the study. This article is protected by copyright. All rights reserved
Quand lâĂ©somĂ©prazole induit une rĂ©sistance Ă la fluindione : une interaction mĂ©connue
National audienc
Hypertension artérielle pulmonaire, moelle osseuse, précurseurs endothéliaux et sérotonine
La sérotonine et les cellules souches dérivées de la moelle osseuse participent de
concert Ă lâhypertension artĂ©rielle pulmonaire. Notre travail a montrĂ© que lâabsence du
récepteur 5-HT2B
génÚre des altérations permanentes de la composition du sang et de la moelle osseuse dans
les lignées myéloïdes et, en particulier, dans les cellules progénitrices endothéliales.
Dans lâhypertension artĂ©rielle pulmonaire (HTAP), les rĂ©cepteurs 5-HT2B portĂ©s par les cellules de la
moelle osseuse jouent un rĂŽle fondamental. Ils contribuent Ă la
différenciation/prolifération/mobilisation des précurseurs endothéliaux de la moelle. Ces
cellules dérivées de la moelle osseuse ont une fonction critique dans le développement de
lâHTAP et du remodelage vasculaire pulmonaire. Ces donnĂ©es indiquent que les cellules de
la moelle osseuse jouent un rĂŽle clĂ© dans la pathogenĂšse de lâHTAP et suggĂšrent que les
interactions entre la sérotonine et BMPR2 (bone morphogenic protein type 2
receptor) pourraient se situer dans la moelle osseuse
PROCĂDĂ POUR LE TRAITEMENT DE MALADIES CARDIAQUES CHEZ DES MAMMIFĂRES
The present invention relates to the use of a serotoninergic receptor antagonist for the treatment and/or prevention of heart damages in mammals.La présente invention concerne l'utilisation d'un antagoniste du récepteur sérotoninergique pour le traitement et/ou la prévention de lésions cardiaques chez les mammifÚres
New therapeutic opportunities for 5-HT2 receptor ligands
International audienceSerotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. Serotonin (5-hydroxytryptamine, 5-HT) mediates numerous physiological functions in the brain and the periphery by activating a variety of receptors. 5-HT receptors are divided into four classes, three of which belong to the G protein-coupled receptor family. This review provides an overview of the recent pharmacological developments involving the Gq-coupled 5-HT2 receptor subfamily as well as the pathological implications of this receptor subfamily with regard to fibrosis, the central nervous system, cardiovascular disorders, and cancer. The final section highlights new therapeutic opportunities and emerging research revealing unexplored medical opportunities for this class of 5-HT receptors. The development of biased 5-HT2 receptor ligands appears to be an interesting topic in various areas. In light of recent discoveries, the need for the development of new and safer drugs should take into account the risk of cardiovascular side effects such as pulmonary hypertension and heart valve disease
Comparison of bioimpedance spectroscopy and X-Ray micro-computed tomography for total fat volume measurement in mice.
Obesity and the metabolic syndrome are two pathologies whose prevalence are in a constant increase. Evaluation of the total fat mass but also of the distribution between visceral and subcutaneous adipose tissue are important factors while assessing the pathophysiology of these two pathologies. Computed tomography (CT) and bioimpedance (BIS) are the translational methods the most frequently used in human beings as well as in rodent models in longitudinal studies on adiposity and obesity. Surprisingly, no direct comparison of micro-CT and BIS was reported yet in mice. Therefore, the present study was carried out to evaluate and compare the accuracy and the uncertainty of measurement of micro-CT and BIS in this species. The proportion of fat mass was measured with BIS, micro-CT and direct post-mortem tissue weight, and correlations between the data were established to evaluate the accuracy of the methods but also the uncertainty of BIS and micro-CT. There were significant correlations between weights of fat tissues on scale and proportion of total fat mass determined by BIS or micro-CT (r = 0.81 and 0.86 respectively) but both methods overestimated the total fat mass, especially in the smallest animals; overestimation of fat mass was amplified with BIS compared to micro-CT. In addition BIS and micro-CT were highly correlated (r = 0.94). Test-test reliability showed a greater variability of the BIS with respect to the micro-CT (coefficient of variation = 17.2 vs 5.6% respectively). Hence, as far as subtle differences between groups or changes within one group are awaited, micro-CT may appear as the most reliable method for determination of fat mass in mice. Micro-CT, unlike BIS, will also allow to qualitatively and quantitatively differentiate between subcutaneous and visceral adipose tissues, which is of major importance in studies on adiposity and its complications