GDF15 and Cardiac Cells: Current Concepts and New Insights

International audienceGrowth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily of proteins. Glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) is an endogenous receptor for GDF15 detected selectively in the brain. GDF15 is not normally expressed in the tissue but is prominently induced by “injury”. Serum levels of GDF15 are also increased by aging and in response to cellular stress and mitochondrial dysfunction. It acts as an inflammatory marker and plays a role in the pathogenesis of cardiovascular diseases, metabolic disorders, and neurodegenerative processes. Identified as a new heart-derived endocrine hormone that regulates body growth, GDF15 has a local cardioprotective role, presumably due to its autocrine/paracrine properties: antioxidative, anti-inflammatory, antiapoptotic. GDF15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and in the heart within hours after myocardial infarction (MI). Recent studies show associations between GDF15, inflammation, and cardiac fibrosis during heart failure and MI. However, the reason for this increase in GDF15 production has not been clearly identified. Experimental and clinical studies support the potential use of GDF15 as a novel therapeutic target (1) by modulating metabolic activity and (2) promoting an adaptive angiogenesis and cardiac regenerative process during cardiovascular diseases. In this review, we comment on new aspects of the biology of GDF15 as a cardiac hormone and show that GDF15 may be a predictive biomarker of adverse cardiac events

Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the xc- GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system xc-, composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage

GDF15 : A modulator of immunity and a predictive biomarker of cardiovascular events : A strategy in COVID-19

International audienceSince January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active

Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin

International audienceCalprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 possess both anti-inflammatory and anti-bacterial properties. The complex is a ligand of the toll-like receptor 4 (TLR4) and receptor for advanced glycation end (RAGE). At sites of infection and inflammation, CLP is a target for oxidation due to its co-localization with neutrophil-derived oxidants. In the heart, oxidative stress (OS) responses and S100 proteins are closely related and intimately linked through pathophysiological processes. Our review summarizes the roles of S100A8, S100A9 and CLP in the inflammation in relationship with vascular OS, and we examine the importance of CLP for the mechanisms driving in the protection of myocardium. Recent evidence interpreting CLP as a critical modulator during the inflammatory response has identified this alarmin as an interesting drug target

Mitochondrial-derived peptides: New markers for cardiometabolic dysfunction

International audienceGreat attention is being paid to the evaluation of new markers in blood circulation for the estimation of tissue metabolism disturbance. This endogenous disturbance may contribute to the onset and progression of cardiometabolic disease. In addition to their role in energy production and metabolism, mitochondria play a main function in cellular mechanisms, including apoptosis, oxidative stress and calcium homeostasis. Mitochondria produce mitochondrial-derived peptides that mediate the transcriptional stress response by translocating into the nucleus and interacting with deoxyribonucleic acid. This class of peptides Abbreviations: ATP, adenosine triphosphate; CMD, coronary microvascular dysfunction; CNTFR, ciliary neuronotrophic factor receptor; DNA, deoxyribonucleic acid; ERK1/2, extracellular signal-regulated kinase 1/2; FPRL1, formyl peptide receptor-like 1; IGF-1, insulin-like growth factor-1; MDPs, mitochondrial-derived peptides; MOTS-c, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c; mtDNA, mitochondrial deoxyribonucleic acid; ROS, reactive oxygen species; SHLP, small humanin-like peptide; STAT3, signal transducer and activator of transcription 3

Multimodal Approach for the Prediction of Atrial Fibrillation Detected After Stroke: SAFAS Study

International audienceBackground: Intensive screening for atrial fibrillation (AF) has led to a better recognition of this cause in stroke patients. However, it is currently debated whether AF Detected After Stroke (AFDAS) has the same pathophysiology and embolic risk as prior-to-stroke AF. We thus aimed to systematically approach AFDAS using a multimodal approach combining clinical, imaging, biological and electrocardiographic markers.Methods: Patients without previously known AF admitted to the Dijon University Hospital (France) stroke unit for acute ischemic stroke were prospectively enrolled. The primary endpoint was the presence of AFDAS at 6 months, diagnosed through admission ECG, continuous electrocardiographic monitoring, long-term external Holter during the hospital stay, or implantable cardiac monitor if clinically indicated after discharge.Results: Of the 240 included patients, 77 (32%) developed AFDAS. Compared with sinus rhythm patients, those developing AFDAS were older, more often women and less often active smokers. AFDAS patients had higher blood levels of NT-proBNP, osteoprotegerin, galectin-3, GDF-15 and ST2, as well as increased left atrial indexed volume and lower left ventricular ejection fraction. After multivariable analysis, galectin-3 9 ng/ml [OR 3.10; 95% CI (1.03-9.254), p = 0.042], NT-proBNP 290 pg/ml [OR 3.950; 95% CI (1.754-8.892, p = 0.001], OPG ≥ 887 pg/ml [OR 2.338; 95% CI (1.015-5.620), p = 0.046) and LAVI ≥ 33.5 ml/m 2 [OR 2.982; 95% CI (1.342-6.625), p = 0.007] were independently associated with AFDAS.Conclusion: A multimodal approach combining imaging, electrocardiography and original biological markers resulted in good predictive models for AFDAS. These results also suggest that AFDAS is probably related to an underlying atrial cardiopathy

Distribution of atrial cardiomyopathy markers and association with atrial fibrillation detected after ischaemic stroke in the SAFAS study

Background Atrial cardiomyopathy (AC) is an emerging concept explaining the pathophysiology of cardioembolic strokes in absence of atrial fibrillation (AF). A definition based on the presence of electrical abnormality (P-wave terminal force in lead V1 (PTFV1) >5000 µV×ms), N-Terminal pro-B-type natriuretic peptide (NT pro BNP) >250 pg/mL and/or indexed left atrial diameter (LADI) >3 cm/m² is currently tested in the ARCADIA (AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke) trial. We set out to estimate the prevalence of AC as defined in the ARCADIA trial, its determinants and its association with AF detected after stroke (AFDAS).Methods Stepwise screening for silent Atrial Fibrillation After Stroke (SAFAS) study prospectively included 240 ischaemic stroke patients. AC markers were complete for 192 of them and 9 were not included in this analysis because AF had been diagnosed on admission.Results A total of 183 patients were analysed, of whom 57% (104 patients) met the AC criteria (79 NT-proBNP, 47 PTFV1, 4 LADI). In the multivariate logistic regression, C reactive protein >3 mg/L (OR (95% CI) 2.60 (1.30 to 5.21), p=0.007) and age (OR (95% CI) 1.07 (1.04 to 1.10), p<0.001) were found to be independently associated with AC. After 6 months of follow-up, AFDAS was detected in 33% of AC patients and in 14% of the remaining ones (p=0.003). However, AC was not independently associated with AFDAS, contrary to left atrial volume index (>34 mL/m2, OR 2.35 (CI 1.09 to 5.06) p=0029).Conclusion AC as defined in ARCADIA is mostly based on NT pro BNP elevation (76% of patients) and is associated with age and inflammation. Moreover, AC was not independently associated with AFDAS at follow-up. The ARCADIA trial, which compares aspirin to apixaban in patients with embolic strokes of undetermined source with AC markers and must, therefore be analysed in the light of these limitations.Trial registration number NCT03570060