La découverte de l’ivabradine (Procoralan®), inhibiteur sélectif du courant pacemaker If : Une nouvelle approche thérapeutique des cardiopathies ischémiques

L’inhibition du courant pacemakerIf est une cible idéale pour réduire de façon sélective la fréquence cardiaque et constitue une approche thérapeutique attractive pour les cardiopathies ischémiques. Les études précliniques montrent que l’ivabradine (Procoralan®) inhibe le courant If du noeud sinusal, réduit de façon sélective la fréquence cardiaque au repos et à l’exercice, respecte la contractilité myocardique, la conduction auriculo-ventriculaire et la repolarisation ventriculaire et limite de façon aussi efficace qu’un β-bloquant l’ischémie myocardique induite par l’exercice, tout en préservant mieux la contractilité myocardique régionale. Ces données ont été confirmées chez l’homme, démontrant, en particulier, l’activité anti-ischémique au moins équivalente à celle d’un β-bloquant chez les patients ayant un angor stable. De grands essais cliniques en cours visent maintenant à déterminer l’intérêt de l’ivabradine dans l’insuffisance cardiaque d’origine ischémique et à tester sa capacité à améliorer le pronostic des cardiopathies ischémiques en réduisant la mortalité et la survenue d’événements cardiovasculaires majeurs.Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries and its prevalence is predicted to grow with the current aging of the population in these countries. In spite of the rapid pace of progress and increasing use of myocardial revascularization procedures, in particular percutaneous coronary interventions, the medical treatment of coronary artery disease has lost none of its relevance in the majority of patients, though conventional drugs have their limitations and the pharmacological approach to ischemic heart disease needs to be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement in quality of life. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most ischemic episodes, but also as an independent predictor of mortality, inhibition of the pacemaker If current in view of inducing a direct and selective decrease in heart rate represents an ideal conceptual target and an attractive therapeutic approach to coronary artery disease. The screening of original benzocycloalkane compounds at the Servier Research Institute resulted in the selection of ivabradine (Procoralan®) for clinical development. Preclinical data showed that ivabradine inhibits the If current originating in the sinus node, induces a selective reduction in heart rate both at rest and during exercise, preserves myocardial contractility, atrioventricular conduction and ventricular repolarization and prevents exercise-induced myocardial ischemia as effectively as a β-blocker while offering better protection of regional myocardial contractility. These data were confirmed in humans, in particular the anti-ischemic efficacy of ivabradine, at least as effective as that of a β-blocker in patients with stable angina. Large ongoing clinical trials are seeking to assess the therapeutic value of ivabradine in ischemic heart failure and its potential for improving the prognosis of coronary artery disease by reducing mortality and the occurrence of major cardiovascular events

Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice

published_or_final_versio

Endothelium-selective activation of AMP-activated protein kinase improves re-endothelialization and vascular function via induction of heme oxygenase-1 in diabetic mice

This journal suppl. entitled: EDHF 2012 - 10th Anniversary MeetingReduced number and impaired function of endothelial progenitor cells (EPCs) exacerbate vascular injury in diabetes. As AMP-activated kinase (AMPK) is a target of several anti-diabetic and cardiovascular drugs, this study investigated whether endothelium-selective activation of AMPK prevents diabetes-induced impairment in endothelial repair and vasoreactivity by impro...postprin

Elevated 20-Hete contributes to the improved endothelial function in lipocalin-2 deficient mice

This journal suppl. entitled: EDHF 2012 - 10th Anniversary MeetingLipocalin-2 is a glycoprotein constitutively secreted from adipocytes. In obese human subjects, the circulating lipocalin-2 level is elevated and positively correlated with systolic arterial blood pressure, dyslipidemia and insulin resistance. In mice, deficiency of lipocalin-2 protects against aging- and obesity-induced endothelial dysfunction and CYP4502C express...postprin

Clinical Study Comparison of a Bayesian Network with a Logistic Regression Model to Forecast IgA Nephropathy

Models are increasingly used in clinical practice to improve the accuracy of diagnosis. The aim of our work was to compare a Bayesian network to logistic regression to forecast IgA nephropathy (IgAN) from simple clinical and biological criteria. Retrospectively, we pooled the results of all biopsies (n = 155) performed by nephrologists in a specialist clinical facility between 2002 and 2009. Two groups were constituted at random. The first subgroup was used to determine the parameters of the models adjusted to data by logistic regression or Bayesian network, and the second was used to compare the performances of the models using receiver operating characteristics (ROC) curves. IgAN was found (on pathology) in 44 patients. Areas under the ROC curves provided by both methods were highly significant but not different from each other. Based on the highest Youden indices, sensitivity reached (100% versus 67%) and specificity (73% versus 95%) using the Bayesian network and logistic regression, respectively. A Bayesian network is at least as efficient as logistic regression to estimate the probability of a patient suffering IgAN, using simple clinical and biological data obtained during consultation

Adaptation of aphid stylectomy for analyses of proteins and mRNAs in barley phloem sap

Sieve tubes are transport conduits not only for photoassimilates but also for macromolecules and other compounds that are involved in sieve tube maintenance and systemic signalling. In order to gain sufficient amounts of pure phloem exudates from barley plants for analyses of the protein and mRNA composition, a previously described stylectomy set-up was optimized. Aphids were placed in sealed cages, which, immediately after microcauterization of the stylets, were flooded with water-saturated silicon oil. The exuding phloem sap was collected with a capillary connected to a pump. Using up to 30 plants and 600 aphids (Rhopalosiphum padi) in parallel, an average of 10 μl of phloem sap could be obtained within 6 h of sampling. In first analyses of the macromolecular content, eight so far unknown phloem mRNAs were identified by cDNA-amplified fragment length polymorphism. Transcripts in barley phloem exudates are related to metabolism, signalling, and pathogen defence, for example coding for a protein kinase and a pathogen- and insect-responsive WIR1A (wheat-induced resistance 1A)-like protein. Further, one-dimensional gel electrophoresis and subsequent partial sequencing by mass spectrometry led to the identification of seven major proteins with putative functions in stress responses and transport of mRNAs, proteins, and sugars. Two of the discovered proteins probably represent isoforms of a new phloem-mobile sucrose transporter. Notably, two-dimensional electrophoresis confirmed that there are >250 phloem proteins awaiting identification in future studies

New Insights in the Contribution of Voltage-Gated Nav Channels to Rat Aorta Contraction

BACKGROUND: Despite increasing evidence for the presence of voltage-gated Na(+) channels (Na(v)) isoforms and measurements of Na(v) channel currents with the patch-clamp technique in arterial myocytes, no information is available to date as to whether or not Na(v) channels play a functional role in arteries. The aim of the present work was to look for a physiological role of Na(v) channels in the control of rat aortic contraction. METHODOLOGY/PRINCIPAL FINDINGS: Na(v) channels were detected in the aortic media by Western blot analysis and double immunofluorescence labeling for Na(v) channels and smooth muscle alpha-actin using specific antibodies. In parallel, using real time RT-PCR, we identified three Na(v) transcripts: Na(v)1.2, Na(v)1.3, and Na(v)1.5. Only the Na(v)1.2 isoform was found in the intact media and in freshly isolated myocytes excluding contamination by other cell types. Using the specific Na(v) channel agonist veratridine and antagonist tetrodotoxin (TTX), we unmasked a contribution of these channels in the response to the depolarizing agent KCl on rat aortic isometric tension recorded from endothelium-denuded aortic rings. Experimental conditions excluded a contribution of Na(v) channels from the perivascular sympathetic nerve terminals. Addition of low concentrations of KCl (2-10 mM), which induced moderate membrane depolarization (e.g., from -55.9+/-1.4 mV to -45.9+/-1.2 mV at 10 mmol/L as measured with microelectrodes), triggered a contraction potentiated by veratridine (100 microM) and blocked by TTX (1 microM). KB-R7943, an inhibitor of the reverse mode of the Na(+)/Ca(2+) exchanger, mimicked the effect of TTX and had no additive effect in presence of TTX. CONCLUSIONS/SIGNIFICANCE: These results define a new role for Na(v) channels in arterial physiology, and suggest that the TTX-sensitive Na(v)1.2 isoform, together with the Na(+)/Ca(2+) exchanger, contributes to the contractile response of aortic myocytes at physiological range of membrane depolarization

Identification of Host Genes Involved in Geminivirus Infection Using a Reverse Genetics Approach

Geminiviruses, like all viruses, rely on the host cell machinery to establish a successful infection, but the identity and function of these required host proteins remain largely unknown. Tomato yellow leaf curl Sardinia virus (TYLCSV), a monopartite geminivirus, is one of the causal agents of the devastating Tomato yellow leaf curl disease (TYLCD). The transgenic 2IRGFP N. benthamiana plants, used in combination with Virus Induced Gene Silencing (VIGS), entail an important potential as a tool in reverse genetics studies to identify host factors involved in TYLCSV infection. Using these transgenic plants, we have made an accurate description of the evolution of TYLCSV replication in the host in both space and time. Moreover, we have determined that TYLCSV and Tobacco rattle virus (TRV) do not dramatically influence each other when co-infected in N. benthamiana, what makes the use of TRV-induced gene silencing in combination with TYLCSV for reverse genetic studies feasible. Finally, we have tested the effect of silencing candidate host genes on TYLCSV infection, identifying eighteen genes potentially involved in this process, fifteen of which had never been implicated in geminiviral infections before. Seven of the analyzed genes have a potential anti-viral effect, whereas the expression of the other eleven is required for a full infection. Interestingly, almost half of the genes altering TYLCSV infection play a role in postranslational modifications. Therefore, our results provide new insights into the molecular mechanisms underlying geminivirus infections, and at the same time reveal the 2IRGFP/VIGS system as a powerful tool for functional reverse genetics studies