La journée citoyenne. La synthèse.

Synthèse des travaux de «La journée des élus» organisée dans le cadre de Foresterranée'99

Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

La journée citoyenne. La synthèse.

International audienceSynthèse des travaux de «La journée des élus» organisée dans le cadre de Foresterranée'99

Ischaemic postconditioning reduces infarct size: systematic review and meta-analysis of randomized controlled trials

International audienceBACKGROUND: Infarct size (IS) is a major determinant of patient outcome after acute ST-segment elevation myocardial infarction (STEMI). Interventions aimed at reducing reperfusion injury, such as cardiac ischaemic postconditioning (IPost), may reduce IS and improve clinical outcomes. IPost has been shown to be feasible in patients with STEMI treated by primary percutaneous coronary intervention (PPCI). AIMS: To provide an updated summary of the efficacy of IPost, assessed by analysing accurate surrogate markers of IS. METHODS: We performed a meta-analysis of randomized controlled trials that evaluated the efficacy of IPost in STEMI patients undergoing PPCI. The main outcome was area under the curve of serum creatine kinase release (CK-AUC). Secondary outcomes were other surrogate biomarkers of IS, complete ST-segment resolution, direct measurement of IS by single-photon emission computed tomography and estimation of IS by cardiac magnetic resonance (CMR-IS). RESULTS: Eleven studies were retrieved, including 1313 STEMI patients undergoing PPCI with or without IPost. Compared with controls, we observed a significant reduction in CK-AUC (standard mean difference [SMD] -2.84 IU/L, 95% CI -5.43 to -0.25 IU/L; P=0.03). Other surrogate markers, such as CMR-IS (SMD -0.36, 95% CI -0.88 to 0.15; P=0.16), showed a non-significant IS reduction in the IPost group. CONCLUSIONS: This meta-analysis, dealing with accurate surrogate markers of IS, suggests that IPost reduces IS. However, results should be interpreted cautiously because of limited sample sizes and significant heterogeneity. Whether this translates into improvements in cardiac function and patient prognosis still needs to be demonstrated in larger prospective randomized controlled studies that are powered sufficiently

Cardiac fibroblasts protect cardiomyocytes against lethal ischemia-reperfusion injury

International audienceRoles of cardiac fibroblasts (CFs) in the regulation of myocardial structure and function have been emphasized in the last decade. Their implications in pathophysiological aspects of chronic heart diseases such as myocardial remodeling and fibrosis are now well established; however their contribution to the acute phase of ischemia-reperfusion injury still remains elusive. We hypothesized that CF may contribute to cardiomyocyte (CM) protection against ischemia-reperfusion injuries. Experiments performed on isolated neonatal rat CF and CM demonstrated that the presence of CF in co-cultures increases CM viability (58 +/- 2% versus 30 +/- 2% in control) against hypoxia-reoxygenation injury, in a paracrine manner. It was confirmed by a similar effect of hypoxic CF secretome alone on CM viability (51 +/- 9% versus 31 +/- 4% in untreated cells). These findings were corroborated by in vivo experiments in a mice model of myocardial infarction in which a 25% infarct size reduction was observed in CF secretome treated mice compared to control. Tissue inhibitor of metalloproteinases-1 (TIMPs-1) alone, abundantly detected in CF secretome, was able to decrease CM cell death (35%) and experiments with pharmacological inhibitors of PI3K/Akt and ERK1/2 pathways provided more evidence that this paracrine protection is partly mediated by these signaling pathways. In vivo experiments strengthened that TIMP-1 alone was able to decrease infarct size (37%) and were validated by depletion experiments demonstrating that CF secretome cardioprotection was abolished by TIMP-1 depletion. Our data demonstrated for the first time that CFs participate in cardioprotection during the acute phase of ischemia-reperfusion via a paracrine pathway involving TIMP-1

Kinetics and prognostic value of soluble VCAM-1 in ST-segment elevation myocardial infarction patients

International audienceBACKGROUND: Soluble vascular cell adhesion molecule-1 (sVCAM-1) is a biomarker of endothelial activation and inflammation. There is still controversy as to whether it can predict clinical outcome after ST-elevation myocardial infarction (STEMI). Our aim was to assess the sVCAM-1 kinetics and to evaluate its prognostic predictive value. METHOD: We prospectively enrolled 251 consecutive STEMI patients who underwent coronary revascularization in our university hospital. Blood samples were collected at admission, 4, 24, 48 h and 1 month after admission. sVCAM-1 serum level was assessed using ELISA assay. All patients had cardiac magnetic resonance imaging at 1-month for infarct size (IS) and left ventricular ejection fraction (LVEF) assessment. Clinical outcomes were recorded over 12 months after STEMI. RESULTS: sVCAM-1 levels significantly increased from admission up to 1 month and were significantly correlated with IS, LVEF, and LV end-systolic and diastolic volume. (H48 area under curve (AUC) ≥ H48 median) were associated with an increased risk of adverse clinical events during the 12-month follow-up period with a hazard ratio (HR) = 2.6 (95% confidence interval [CI] of ratio = 1.2-5.6, p = .02). The ability of H48 AUC for sVCAM-1 to discriminate between patients with or without the composite endpoint was evaluated using receiver operating characteristics with an AUC at 0.67 (0.57-0.78, p = .004). This ability was significantly superior to H48 AUC creatine kinase (p = .03). CONCLUSIONS: In STEMI patients, high sVCAM-1 levels are associated with a poor clinical outcome. sVCAM-1 is an early postmyocardial infarction biomarker and might be an interesting target for the development of future therapeutic strategies

Safety and efficacy of drug eluting stents vs bare metal stents in patients with atrial fibrillation: A systematic review and meta-analysis

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