Role of humanin ; a mitochondrial-derived peptide, in cardiovascular disorders

International audienc

The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases

International audienceAmong the numerous molecules that are being studied for their potential utility as biomarkers of cardiovascular diseases, much interest has been shown in the superfamily of tumor necrosis factor (TNF) receptors. Members of this family include osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). These signals may be expressed and regulated, and their functions could be involved in several physiological and pathological processes. The relationship between bone regulatory proteins and vascular biology has attracted attention, and it has been suggested that OPG may mediate vascular calcification and cardiometabolic diseases. OPG is steadily released from vascular endothelial cells in response to inflammatory stimuli, suggesting that it plays a modulatory role in vascular injury, inflammation, and atherosclerosis. Vascular calcification, a hallmark of atherosclerosis, is similar to bone remodeling. It is an actively regulated mechanism that includes both inductive and inhibitory processes. There is a temporal link between the development of osteoporosis and vascular calcification, which is particularly marked in post-menopausal women and the elderly. The precise nature of the link between bone metabolism, vascular calcification and cardiovascular disease is largely unknown but increasing evidence suggests that the triad of RANK/RANKL/OPG may be important in the initiation of various diseases. An increased release of OPG is associated with increased cardiovascular risk and it is suggested that increased OPG levels resulting from vascular damage correspond to a protective mechanism. Circulating OPG levels could be used as independent biomarkers of cardiovascular disease in patients with acute or chronic cardiometabolic disease and thus an improved prognosi

Ischemic stroke increases heart vulnerability to ischemia-reperfusion and alters myocardial cardioprotective pathways

International audienceBackground and Purpose-For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo, and how they influence cardiac vulnerability to ischemia-reperfusion (IR) injury. Methods-Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue staining and assessment of neurological deficit 2h, 24h and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to IR injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LV) were analyzed with western blotting and quantitative RT-PCR. Results-Our stroke model produced large cerebral infarcts with severe neurological deficit. Cardiac contractile dysfunction was observed with an early but persistent reduction of LV fractional shortening in vivo and of LV developed pressure (LVDevP) ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LVDevP and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 and cardioprotective SAFE signaling pathways. Conclusions-Our findings indicate that stroke not only impairs cardiac contractility and also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms o

Intérêt du Growth Differentiation Factor 15 (GDF15) comme biomarqueur pronostique après la survenue d’un accident vasculaire cérébral ischémique (AVC)

International audienceIntroductionLe GDF15 est un biomarqueur de mauvais pronostic dans certaines pathologies cardiovasculaires comme le syndrome coronarien aigu. Son intérêt dans le domaine de AVC n’a été que peu étudié à ce jour.ObjectifsNotre travail consistait à l’évaluation des taux de GDF15 chez des patients hospitalisés à la phase aiguë d’un AVC ischémique traités par fibrinolyse et/ou thrombectomie. L’objectif principal était d’évaluer l’association entre les taux de GDF15 et la récupération fonctionnelle à 3 mois.MéthodesAu total, 174 patients ont été inclus entre le 16/01 et le 30/09/2017. Le consentement était recueilli oralement. Des prélèvements biologiques ont été réalisés à l’admission du patient (j0), à j1, j3 et j7. Les taux plasmatiques de GDF15 étaient mesurés par méthode Elisa. Les patients étaient recontactés par téléphone à 3 mois afin d’évaluer le score de Rankin.RésultatsLes moyennes des taux plasmatiques de GDF15 à j0, j1, j3 et j7 étaient significativement plus élevées chez les patients avec un score de Rankin ≥ 2 par rapport aux patients avec un score de Rankin à 0 ou 1. En analyse de régression logistique univariée, il a été retrouvé une augmentation significative de l’odd ratio (OR) concernant le risque d’avoir un score de Rankin ≥ 2 en ayant un taux de GDF15 situé dans le dernier tertile. Les taux de GDF15 étaient significativement plus élevés chez les patients traités par thrombectomie.DiscussionDans la littérature, seulement deux études se sont intéressées au GDF15 en tant que biomarqueur pronostique après la survenue d’un AVC ischémique. Notre travail est le premier à étudier l’évolution des taux de GDF15 dans un groupe défini de patients bénéficiant d’un traitement de revascularisation. L’expression du GDF15 semble modifiée en fonction du traitement reçu : fibrinolyse ou thrombectomie.ConclusionCe travail montre des résultats concordants avec les quelques données actuellement disponibles dans la littérature. Le GDF15 apparaît comme un biomarqueur de mauvais pronostic après la survenue d’un AVC ischémique

Experimental cerebral ischemia in rats increases myocardial vulnerability to ischemia-reperfusion injury ex vivo

IF 4.066International audienc

The Role of Osteoprotegerin in Vascular Calcification and Bone Metabolism: The Basis for Developing New Therapeutics

International audienc

The Role of Osteoprotegerin and Its Ligands in Vascular Function

International audienceThe superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future

Mitochondrial SLC25 Carriers: Novel Targets for Cancer Therapy

International audienceThe transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy

Association Between Growth Differentiation Factor-15 and Heart Failure Complicating Acute Myocardial Infarction

International audienceBackground-Growth differentiation factor-15 (GDF15) is an emerging biomarker in cardiovascular diseases. We aimed to evaluate the association of GDF15 levels at admission with HF occurrence during hospitalization for acute myocardial infarction (AMI). Methods-Our prospective study included all patients admitted from June 2016 to February 2018 for type 1 AMI in the coronary care unit of the Dijon-Bourgogne University Hospital. In-hospital severe heart failure (HF) was defined as Killip class >2. Serum levels of GDF15 were obtained from blood samples were taken on admission. Results-Among the 284 AMI patients, median age was 67 years, and 27% were women. GDF15 levels were strongly correlated with age and positively correlated with most cardiovascular risk factors (hypertension and diabetes) and inflammation (CRP>3 mg/L). When compared with patients without HF (274/284), GDF15 in patients with inhospital HF (10/284) was more than two time