The N-end rule pathway is a sensor of heme

The conjugation of arginine, by arginyl-transferase, to N-terminal aspartate, glutamate or oxidized cysteine is a part of the N-end rule pathway of protein degradation. We report that arginyl-transferase of either the mouse or the yeast Saccharomyces cerevisiae is inhibited by hemin (Fe3+-heme). Furthermore, we show that hemin inhibits arginyl-transferase through a redox mechanism that involves the formation of disulfide between the enzyme's Cys-71 and Cys-72 residues. Remarkably, hemin also induces the proteasome-dependent degradation of arginyl-transferase in vivo, thus acting as both a "stoichiometric" and "catalytic" down-regulator of the N-end rule pathway. In addition, hemin was found to interact with the yeast and mouse E3 ubiquitin ligases of the N-end rule pathway. One of substrate-binding sites of the yeast N-end rule's ubiquitin ligase UBR1 targets CUP9, a transcriptional repressor. This site of UBR1 is autoinhibited but can be allosterically activated by peptides that bear destabilizing N-terminal residues and interact with two other substrate-binding sites of UBR1. We show that hemin does not directly occlude the substrate-binding sites of UBR1 but blocks the activation of its CUP9-binding site by dipeptides. The N-end rule pathway, a known sensor of short peptides, nitric oxide, and oxygen, is now a sensor of heme as well. One function of the N-end rule pathway may be to coordinate the activities of small effectors, both reacting to and controlling the redox dynamics of heme, oxygen, nitric oxide, thiols, and other compounds, in part through conditional degradation of specific transcription factors and G protein regulators

: Gender differences in STEMI

International audienceBACKGROUND: Gender differences in presentation, management and outcome in patients with ST-segment elevation myocardial infarction (STEMI) have been reported. AIM: To determine whether female gender is associated with higher inhospital mortality. METHODS: Data from ORBI, a regional STEMI registry of 5 years' standing, were analysed. The main data on presentation, management, inhospital outcome and prescription at discharge were compared between genders. Various adjusted hazard ratios were then calculated for inhospital mortality (women versus men). RESULTS: The analysis included 5000 patients (mean age 62.6±13 years), with 1174 women (23.5%). Women were on average 8 years older than men, with more frequent co-morbidities. Median ischaemia time was 215 minutes (26 minutes longer in women; P<0.05). Reperfusion strategies in women less frequently involved fibrinolysis, coronary angiography, radial access and thrombo-aspiration. Female gender, especially in patients aged<60 years, was associated with poorer inhospital prognosis (including higher inhospital mortality: 9% vs. 4% in men; P<0.0001), and underutilization of recommended treatments at discharge. Moreover, excess female inhospital mortality was independent of presentation, revascularization time and reperfusion strategy (hazard ratio for women 1.33, 95% confidence interval 1.01-1.76; P=0.04). CONCLUSIONS: One in four patients admitted for STEMI was female, with significant differences in presentation. Female gender was associated with less-optimal treatment, both in the acute-phase and at discharge. Efforts should be made to reduce these differences, especially as female gender was independently associated with an elevated risk of inhospital mortality

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

EVALUATION ANGIOSCINTIGRAPHIQUE DES EFFETS DE LA RESYNCHRONISATION VENTRICULAIRE PAR STIMULATION MULTISITE DANS L'INSUFFISANCE CARDIAQUE REFRACTAIRE

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation

International audienc

008: Management of ST-elevation myocardial infarction in octogenarian patients. Data from ORBI, a prospective registry of 5000 patients

PurposeTo determine the actual management of ST-elevation myocardial infarction (STEMI) in octogenarian patients and more.MethodsWe analyzed data collected in “ORBI”, a 6 years prospective registry of STEMI patients admitted within 24h of symptoms onset to an interventional cardiology centre of Brittany (France). Main data about management and intra hospital outcome were compared between patients older (Group 1) and younger (Group 2) than 80.Results550 of the 5000 patients (11%, mean age 84.6 ±3) constituted group 1, with a larger female prevalence (51 vs 20% in group 2, p<0.0001). Group 1 had a much longer median delay between onset of symptom and call for medical assistance (65 vs 45min.), and between admission and reperfusion (53 vs 45min.). Table 1 presents data about the management in the 2 groups, both in the acute phase and at discharge. Last, intra hospital mortality is much higher in group 1 (16.5 vs 4.1%, p<0.0001).ConclusionsOctogenarian patients and more represent a large part of patient treated for STEMI, with significant differences in their presentation and management, and a high mortality.Table 1 – *Percentages are calculated only in patients undergoing coronary angiography.Group 1 >80years old n=550Group 2 ≤ 80 years old _=4450Initial managementFibrinolysis38 (7%)723 (16%)<0.0001GP IIb/IIIa receptor inhibitors223 (40%)2674 (60%)<0.0001Coronary angiography493 (89%)4402 (99%)<0.0001Radial access*140 (28%)1511 (34%)<0.0001Primary angioplasty*386 (78%)3197 (72%)0.4Thrombo aspiration*163 (33%)1874 (42%)<0.0001Intra hospital outcomeHigh degree AV block40 (7%)140 (3%)<0.0001Atrial fibrillation59 (10%)161 (3.6%)<0.0001Left ventricular ejection fraction (%)47.2±1250.6±10<0.0001Total length of stay (days)8.2±56.8±4<0.0001Prescription at dischargeAspirine439 (95,6%)4167 (97,7%)0,007Clopidogrel/Prasugrel413 (90,0%)4086 (95,8%)<0,0001β blockers394 (85,8%)3895 (91,3%)<0,0001ACE inhibitor290 (63,2%)2853 (66,9%)0,1Statine373 (81,3%)4057 (95,1%)<0,0001Cardiovascular rehabilitation22 (5,3%)1822 (46,6%)<0,000

TCT-130 Complete Myocardial Revascularisation is not Associated with a Better Prognosis in Cardiogenic Shock Complicating ST-Elevation Myocardial Infarction. Insight from the multicenter prospective ORBI registry

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