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In the recently published manuscript entitled "GDF15 a rising modulator of immunity and a strategy in Coronavirus disease 2019 (COVID-19) in relationship with iron metabolism" and we examined the potential properties of Growth and differentiation factor 15 (GDF15) as an emerging modulator of immunity in COVID-19. We commented new aspects of the biology of GDF15 and investigated the potential value of GDF15 as a biomarker. Is GDF15 a biomarker of the inflammatory process and oxidative stress state? Recently, it was reported that 1500 clinical trials related to COVID-19 have been registered, but none have yet found an optimal strategy. In these conditions, more clinical studies are needed before any of these agents can be considered antiviral agents.

International audience; We aimed to compare retinal vascular density in optical coherence tomography Angiography (oct-A) between patients hospitalized for acute coronary syndrome (AcS) and control patients and to investigate correlation with angiogenesis biomarkers. patients hospitalized for an acute coronary syndrome (AcS) in the intensive care Unit were included in the "high cardiovascular risk" group while patients without cardiovascular risk presenting in the ophthalmology department were included as "control". Both groups had blood sampling and OCT-A imaging. Retina microvascularization density in the superficial capillary plexus was measured on 3 × 3 mm angiograms centered on the macula. Angiopoietin-2, TGF-β1, osteoprotegerin, GDF-15 and ST-2 were explored with ELISA or multiplex method. Overall, 62 eyes of ACS patients and 42 eyes of controls were included. ACS patients had significantly lower inner vessel length density than control patients (p = 0.004). A ROC curve found that an inner vessel length density threshold below 20.05 mm −1 was moderately associated with AcS. Significant correlation was found between serum levels of angiopoietin-2 and osteoprotegerin, and retinal microvascularization in OCT-A (R = − 0.293, p = 0.003; R = − 0.310, p = 0.001). Lower inner vessel length density measured with oct-A was associated with AcS event and was also correlated with higher concentrations of angiopoietin-2 and osteoprotegerin. In spite of the improvements in diagnosis and treatment of cardiovascular diseases (CVD), aging of population and urbanization make CVD one of the world's major disease burdens 1,2. Indeed, CVD remain a main cause of premature deaths and disability worldwide, with an estimated 16.7 million deaths in 2010, and projections show an overwhelming 23.3 million by 2030 3. Cardiovascular risk factors such as hypertension, hypercholesterolemia, and diabetes mellitus lead to systemic inflammation, vascular and cardiac oxidative stress, which contribute to coronary dysfunction and microvascular impairment 4. Thus, coronary macro and microvascular alterations are closely associated and together contribute to the pathophysiology of myocardial ischemia 5. The assessment of myocardial microvascularization is then of major interest in order to estimate the risk of acute coronary events; however, only invasive procedures, using intra vascular contrast agents, are currently available 6 .

The mitochondria produce specific peptides-mitochondrial-derived peptides-that mediate the transcriptional stress response by their translocation into the nucleus and interaction with deoxyribonucleic acid. Mitochondrial-derived peptides are regulators of metabolism. This class of peptides comprises humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides (SHLPs). Humanin inhibits mitochondrial complex 1 activity and limits the level of oxidative stress in the cell. Data show that mitochondrial-derived peptides have a role in improving metabolic diseases, such as type 2 diabetes. Perhaps humanin can be used as a marker for mitochondrial function in cardiovascular disease or as a pharmacological strategy in patients with endothelial dysfunction. The goal of this review is to discuss the newly emerging functions of humanin, and its biological role in cardiovascular disorders.

BackgroundIntensive 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.MethodsPatients 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.ResultsOf 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/m2 [OR 2.982; 95% CI (1.342–6.625), p = 0.007] were independently associated with AFDAS.ConclusionA 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.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03570060].

(1) Background: The limited availability of thrombectomy-capable stroke centres raises questions about pre-hospital triage of patients with suspected stroke (IS) due to large vessel occlusion (LVO). Aims: This study aimed to evaluate the diagnostic accuracy of clinical stroke severity scales available for LVO detection. (2) Methods: Patients with IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013–2017). Clinical signs and arterial imaging data were collected. LVO was defined as an occlusion site affecting the terminal intracranial internal carotid artery, the M1 segment of the middle cerebral artery (MCA), or the basilar artery (restricted definition). A wide definition of LVO also included the M2 segment of the MCA. For each of the 16 evaluated scales, a receiver operator characteristic (ROC) analysis was performed, and the c-statistic representing the area under the ROC curve was evaluated to assess discrimination for predicting LVO. (3) Results: 971 patients were registered, including 123 patients (12.7%) with an LVO according to the restricted definition. The c-statistic for LVO detection ranged between 0.66 and 0.80 according to the different scales, with a sensibility varying from 70% to 98% and a specificity from 33% to 86%. According to the wide definition of LVO (174 patients, 17.9%), the c-statistic was slightly lower, ranging between 0.64 and 0.79. The sensitivity was 59% to 93%, and the specificity was 34% to 89%. (4) Conclusion: The clinical scales failed to combine a high sensitivity and a high specificity to detect LVO. Further studies are needed to determine the best strategy for pre-hospital triage of IS patients.

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.

We evaluated whether pre-existing brain damage may explain greater severity in cognitively-impaired patients with ischemic stroke (IS).IS patients were retrieved from the population-based registry of Dijon, France. Pre-existing damage (leukoaraiosis, old vascular brain lesions, cortical and central brain atrophy) was assessed on initial CT-scan. Association between prestroke cognitive status defined as no impairment, mild cognitive impairment (MCI), or dementia, and clinical severity at IS onset assessed with the NIHSS score was evaluated using ordinal regression analysis. Mediation analysis was performed to assess pre-existing brain lesions as mediators of the relationship between cognitive status and severity.Among the 916 included patients (mean age 76.8 ± 15.0 years, 54.3% women), those with pre-existing MCI (n = 115, median NIHSS [IQR]: 6 [2-15]) or dementia (n = 147, median NIHSS: 6 [3-15]) had a greater severity than patients without (n = 654, median NIHSS: 3 [1-9]) in univariate analysis (OR=1.69; 95% CI: 1.18-2.42, p = 0.004, and OR=2.06; 95% CI: 1.49-2.84, p 0.001, respectively). Old cortical lesion (OR=1.53, p = 0.002), central atrophy (OR=1.41, p = 0.005), cortical atrophy (OR=1.90, p 0.001) and moderate (OR=1.41, p = 0.005) or severe (OR=1.84, p = 0.002) leukoaraiosis were also associated with greater severity. After adjustments, pre-existing MCI (OR=1.52; 95% CI: 1.03-2.26, p = 0.037) or dementia (OR=1.94; 95% CI: 1.32-2.86, p = 0.001) remained associated with higher severity at IS onset, independently of confounding factors including imaging variables. Association between cognitive impairment and severity was not mediated by pre-existing visible brain damages.Impaired brain ischemic tolerance in IS patients with prior cognitive impairment could involve other mechanisms than pre-existing visible brain damage.

miRNA-132/212 are small regulators of gene expression with a function that fulfills a vital function in diverse biological processes including neuroprotection of cells with prolonged longevity in neurons and the cardiovascular system. In neurons, miRNA-132 appears to be essential for controlling differentiation, development, and neural functioning. Indeed, it also universally promotes axon evolution, nervous migration, plasticity as well, it is suggested to be neuroprotective against neurodegenerative diseases. Moreover, miRNA-132/212 disorder leads to neural developmental perturbation, and the development of degenerative disorders covering Alzheimer’s, Parkinson’s, and epilepsy’s along with psychiatric perturbations including schizophrenia. Furthermore, the cellular mechanisms of the miRNA-132/212 have additionally been explored in cardiovascular diseases models. Also, the miRNA-132/212 family modulates cardiac hypertrophy and autophagy in cardiomyocytes. The protective and effective clinical promise of miRNA-132/212 in these systems is discussed in this review. To sum up, the current progress in innovative miRNA-based therapies for human pathologies seems of extreme concern and reveals promising novel therapeutic strategies.

Great 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 includes humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides. Mitochondrial-derived peptides are regulators of metabolism, exerting cytoprotective effects through antioxidative stress, anti-inflammatory responses and antiapoptosis; they are emerging biomarkers reflecting mitochondrial function, and the circulating concentration of these proteins can be used to diagnose cardiometabolic dysfunction. The aims of this review are: (1) to describe the emerging role for mitochondrial-derived peptides as biomarkers; and (2) to discuss the therapeutic application of these peptides.

International audience; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an ‘inflammation-induced central mediator of tissue tolerance’ via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.

International audience; Background. Osteoprotegerin (OPG), a glycoprotein of the tumour necrosis factor (TNF) superfamily, is one of the main biomarkers for vascular calcification. Aim. We aimed to evaluate the association between serum OPG levels and extent of coronary lesions in patients with acute myocardial infarction (MI). Methods. Consecutive patients hospitalized for an acute MI who underwent coronary angiography were included. SYNTAX score was calculated to assess the severity of coronary artery disease. The population was analysed in low (5 (3–6)), medium (11 (9–13)) and high (20 (18–23)) tertiles of SYNTAX score. Results. Among the 378 patients included, there was a gradual increase in age, rate of diabetes, anterior wall location, and a reduction in left ventricular ejection fraction across the SYNTAX tertiles. OPG levels significantly increased across the tertiles (962 (782–1497), 1240 (870–1707), and 1464 (1011–2129) pg/mL, respectively (p < 0.001)). In multivariate analysis, OPG [OR(CI95%): 2.10 (1.29–3.49) 0.003], were associated with the high SYNTAX group, beyond hypercholesterolemia, CV history and reduced glomerular filtration rate. Conclusion. We found an association between OPG levels and coronary lesions complexity patients with acute MI.

Osteoporosis (OP) and cardiovascular diseases (CVD) are both important causes of mortality and morbidity in aging patients. There are common mechanisms underlying the regulation of bone remodeling and the development of smooth muscle calcification; a temporal relationship exists between osteoporosis and the imbalance of mineral metabolism in the vessels. Vascular calcification appears regulated by mechanisms that include both inductive and inhibitory processes. Multiple factors are implicated in both bone and vascular metabolism. Among these factors, the superfamily of tumor necrosis factor (TNF) receptors including osteoprotegerin (OPG) and its ligands has been established. OPG is a soluble decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG binds to RANKL and TRAIL, and inhibits the association with their receptors, which have been labeled as the receptor activator of NF-kB (RANK). Sustained release of OPG from vascular endothelial cells (ECs) has been demonstrated in response to inflammatory proteins and cytokines, suggesting that OPG/RANKL/RANK system plays a modulatory role in vascular injury and inflammation. For the development of potential therapeutic strategies targeting vascular calcification, critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism.

Childhood cancer causes immense upheaval for the child and his or her family. The end of the treatments constitutes a transition period which brings with it numerous other problems. It is essential to take into account the difficulties expressed by families and to envisage areas of action to help and support them.

It remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up.From September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP10 mg/L (p 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up.In this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited.

Simple Summary Protons (H+) and molecular hydrogen (H2) in the cell are critical in a wide variety of processes. New cancer treatment uses H2, a biologically inactive gas. H2 can rapidly penetrate cell membranes and reach subcellular components to protect nuclear DNA and mitochondria. H2 reduces oxidative stress, exerts anti-inflammatory effects, and acts as a modulator of apoptosis. Exogenous H2 is a protective therapy that can be used in cancer. Cyclotrons and synchrotrons are currently used to produce protons. Proton beam radiotherapy (PBT) offers great promise for the treatment of a wide variety of cancers. H2 and different types of H2 donors may represent a novel therapeutic strategy in cancer treatment. Abstract Understanding the structure and dynamics of the various hydrogen forms has been a subject of numerous studies. Protons (H+) and molecular hydrogen (H2) in the cell are critical in a wide variety of processes. A new cancer treatment uses H2, a biologically inactive gas. Due to its small molecular weight, H2 can rapidly penetrate cell membranes and reach subcellular components to protect nuclear DNA and mitochondria. H2 reduces oxidative stress, exerts anti-inflammatory effects, and acts as a modulator of apoptosis. Exogenous H2, administered by inhalation, drinking H2-rich water, or injecting H2-rich saline solution, is a protective therapy that can be used in multiple diseases, including cancer. In particle therapy, cyclotrons and synchrotrons are the accelerators currently used to produce protons. Proton beam radiotherapy (PBT) offers great promise for the treatment of a wide variety of cancers due to the sharp decrease in the dose of radiation at a defined point. In these conditions, H2 and different types of H2 donors may represent a novel therapeutic strategy in cancer treatment.

Objective: We assessed the association between pre-stroke cognitive status and 90-day case-fatality. Methods: Patients with ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH) were prospectively identified among residents of Dijon, France, between 2013 and 2015, using a population-based registry. Association between pre-stroke cognitive status and case-fatality at 90 days was evaluated using Cox regression. Results: Seven hundred sixty-two patients were identified, and information about pre-stroke cognitive status was obtained for 716 (92.6%) of them, including 603 IS (84.2%) and 113 ICH (15.8%). Before stroke, 99 (13.8%) patients had mild cognitive impairment (MCI) and 98 (13.7%) had dementia. Patients with cognitive impairment were older, had a higher prevalence of several risk factors, more severe stroke, more frequent ICH, and less admission to stroke unit. Case-fatality rate at 90 days was 11.7% in patients without cognitive impairment, 32.3% in MCI patients, and 55.1% in patients with dementia. In multivariable analyses, pre-existing MCI (hazard ratio [HR] 2.22, 95% CI 1.21–4.05, p = 0.009) and dementia (HR 4.35, 95% CI 2.49–7.61, p < 0.001) were both associated with 90-day case-fatality. Conclusion: Pre-stroke MCI and dementia were both associated with increased mortality. These associations were not fully explained by baseline characteristics, pre-stroke dependency, stroke severity or patient management, and underlying reasons need to be investigated.

International audience; Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily proteins. GDF15 acts as an inflammatory marker, and it plays a role in pathogenesis of tumors, ischemic diseases, metabolic disorders, and neurodegenerative processes. GDF15 is not normally expressed in the tissue; it is prominently induced following 'injury'. GDF15 functions are critical for the regulation of endothelial adaptations after vascular damage. Recently, four research groups simultaneously identified glial-derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL) in the brain, an orphan receptor as the receptor for GDF15, signaling through the coreceptor RET. In this article, new aspects of the biology of GDF15 and receptor GFRAL, and their relationship with various pathologies, are commented on.

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International audience; The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.

International audience; Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short-and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Obesity and related metabolic dysregulation are risk factors for many types of cancer. The interactions between a developing tumor and its microenvironment are known to implicate a complex "crosstalk" among the factors produced by the population of cells. Among these factors, Growth and differentiation factor 15 (GDF15) has a functional role in cancer. GDF15 expression is induced in response to the conditions associated with cellular stress and diseases. The GDF15 receptor, a member of the glial-cell-derived neurotropic factor family (GDNF), is a GDNF family receptor α-like (GFRAL) protein. GDF15 induces pro-angiogenic effects in tumors. However, GDF15 could affect tumorigenesis both positively and negatively. With a better understanding of the upstream disease pathways reflected by GDF15, new treatment targets may emerge.

International audience; Among 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 prognosis