Cardiac Muscarinic Receptor Overexpression in Sudden Infant Death Syndrome

BACKGROUND: Sudden infant death syndrome (SIDS) remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims. The cardiac level of expression of muscarinic receptors, as well as acetylcholinesterase enzyme activity were investigated. METHODOLOGY/PRINCIPAL FINDINGS: Left ventricular samples and blood samples were obtained from autopsies of SIDS and children deceased from non cardiac causes. Binding experiments performed with [(3)H]NMS, a selective muscarinic ligand, in cardiac membrane preparations showed that the density of cardiac muscarinic receptors was increased as shown by a more than doubled B(max) value in SIDS (n = 9 SIDS versus 8 controls). On average, the erythrocyte acetylcholinesterase enzyme activity was also significantly increased (n = 9 SIDS versus 11 controls). CONCLUSIONS: In the present study, it has been shown for the first time that cardiac muscarinic receptor overexpression is associated with SIDS. The increase of acetylcholinesterase enzyme activity appears as a possible regulatory mechanism

Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity

BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. METHODOLOGY/PRINCIPAL FINDINGS: Cardiac muscarinic M(2) and M(3) receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M(2) receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M(2) receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M(2) receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M(2) receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. CONCLUSIONS/SIGNIFICANCE: The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS

The Transcriptome of Human Epicardial, Mediastinal and Subcutaneous Adipose Tissues in Men with Coronary Artery Disease

The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases.Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects.Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD

Syndrome des jambes sans repos (connaissances et traitements)

Le syndrome des jambes sans repos (SJSR), également connu sous le nom de maladie de Willis Ekbom, est un désordre sensori-moteur qui se caractéris par le besoin impérieux de bouger, dans la majorité des cas les jambes. Ce syndrome est déclenché ou aggravé par le repos, soulagé par le mouvement, et se manifeste le plus souvent le soir ou la nuit. De nombreux troubles sont associés au SJSR : insomnie, irratibilité, somnolence diurne. La physiopathologie du SJSR reste encore peu connue. Un déficit en dopamine et en fer semble fortement impliqué. Actuellement, une seule molécule possède une AMM pour le traitement du SJSR. Il s'agit d'un agoniste dopaminergique, la rotigotine. D'autres stratégies thérapeutiques sont proposées en seconde infection telles que les antiépileptiques, les dérivés opiacés et les benzodiazépines. L'efficacité de ces différents traitements reste relativement faible. Cette thèse se propose de faire le point sur l'état des connaissances et des thérapies du SJSR.STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Protective effects of the imidazoline-like drug lnp599 in a marmoset model of obesity-induced metabolic disorders

International audienc

0260 Imidazoline I1 receptor ligands activate hepatic adiponectin pathways and thus improve insulin sensitivity

Metabolic syndrome is defined as a cluster of cardiovascular and metabolic disorders. Previous studies in rat models of metabolic syndrome have demonstrated that ligands selective for I1 imidazoline receptor (LNPs) increase insulin sensitivity through central sympathoinhibition and an additional peripheral effect attributable to adiponectin, a major insulin-sensitizer adipokine. The objective of this study was to explore possible direct actions on hepatocytes, one of the target cells of insulin and adiponectin.Experiments were carried out in HepG2 cells, a cell line of hepatocytes. In order to evaluate the effect of LNPs on insulin sensitivity, the activation (i.e. phosphorylation) of a key actor of insulin pathways, AKT, was evaluated by measuring the ratio pAKT/AKT by Western Blot. Similarly, the effect of LNPs on adiponectin signaling was evaluated by measuring the rate of phosphorylation of the central kinase involved in adiponectin pathways, AMPK, by Western Blot. Insulin (10μM) induced the phosphorylation of AKT (pAKT/ AKT=0.49±0.16) compared to control without insulin (pAKT/AKT=0.11±0.03; p≤0.05) whereas LNPs (1μM) alone did not. Interestingly, pretreatment by LNPs (1μM) during 60 min could potentiate the insulin-induced activation of AKT: LNP509: pAKT/AKT=1.13±0.18 (p≤0.05 vs insulin alone); LNP599: pAKT/AKT=1.23±0.16 (p=0.0545 vs insulin alone).Concerning adiponectin signaling pathways, LNPs alone (from 10−9M to 10−4M) increased AMPK phosphorylation in a concentration- and time-dependent manner. The maximal effect was obtained after 10 min exposure of LNPs 10μM (untreated cells: pAMPK/AMPK=0.18±0.04; LNP 509 pAMPK/ AMPK=0.38±0.05 p≤0.05; LNP599 pAMPK/AMPK=0.46±0.17). These data suggest that LNPs on hepatic cells activate adiponectin pathways and potentiate insulin action. These two direct effects on insulin sensitive cells could account for the ameliorated insulin sensitivity observed in vivo