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1.
PLoS One ; 19(7): e0307105, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39008451

RESUMO

BACKGROUND AND PURPOSE: Growth differentiation factor 15 (GDF15) has emerged as a promising biomarker in cerebro-cardiovascular disease, particularly in acute and chronic inflammatory stress situations. However, understanding the origins, targets and functions of GDF15 in clinical situations, such as ischemic stroke, remains a complex challenge. This study aims to assess the sources of GDF15 production following an experimental ischemic stroke. METHODS: Adult male Wistar rats underwent cerebral embolization through microspheres injection into the left or right internal carotid artery. Two hours post-surgery, GDF15 expression was analyzed in the brain, blood, lungs, liver and heart using quantitative RT-PCR and Western blotting. RESULTS: Stroke model induced large cerebral infarcts accompanied by severe neurological deficits. GDF15 gene expression exhibited a substantial increase in the ipsilateral cortex and cerebellum, with a lesser extent in the contralateral cortex. Regarding GDF15 protein expression, proGDF15 levels were elevated in the 3 aforementioned organs mentioned and the heart. However, the mature form of GDF15 was exclusively present and increased in the heart. Finally, the expression of GDF15 expression was correlated with the neurological deficit score. CONCLUSIONS: Our findings suggest that both the GDF15 gene and pro-protein are expressed in the ischemic brain after a stroke, while only its mature form is expressed remotely in in the heart. The impact of increased GDF15 in the heart following a stroke remains to be established. This is particularly relevant in understanding its relationships with poor neurological outcomes, determining whether it may contribute to stroke-induced cardiac dysfunction.


Assuntos
Fator 15 de Diferenciação de Crescimento , Ratos Wistar , Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Animais , Masculino , Ratos , AVC Isquêmico/metabolismo , AVC Isquêmico/genética , AVC Isquêmico/complicações , Modelos Animais de Doenças , Encéfalo/metabolismo , Encéfalo/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/genética
2.
Int J Mol Sci ; 25(3)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38339161

RESUMO

Physical exercise (EX) is well established for its positive impact on brain health. However, conventional EX may not be feasible for certain individuals. In this regard, this study explores electromyostimulation (EMS) as a potential alternative for enhancing cognitive function. Conducted on both human participants and rats, the study involved two sessions of EMS applied to the quadriceps with a duration of 30 min at one-week intervals. The human subjects experienced assessments of cognition and mood, while the rats underwent histological and biochemical analyses on the prefrontal cortex, hippocampus, and quadriceps. Our findings indicated that EMS enhanced executive functions and reduced anxiety in humans. In parallel, our results from the animal studies revealed an elevation in brain-derived neurotrophic factor (BDNF), specifically in the hippocampus. Intriguingly, this increase was not associated with heightened neuronal activity or cerebral hemodynamics; instead, our data point towards a humoral interaction from muscle to brain. While no evidence of increased muscle and circulating BDNF or FNDC5/irisin pathways could be found, our data highlight lactate as a bridging signaling molecule of the muscle-brain crosstalk following EMS. In conclusion, our results suggest that EMS could be an effective alternative to conventional EX for enhancing both brain health and cognitive function.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Condicionamento Físico Animal , Humanos , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transdução de Sinais/fisiologia , Músculos/metabolismo , Condicionamento Físico Animal/fisiologia , Encéfalo/metabolismo , Fibronectinas/metabolismo
3.
Int J Mol Sci ; 25(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38279218

RESUMO

The positive effects of physical exercise (EX) are well known to be mediated by cerebral BDNF (brain-derived neurotrophic factor), a neurotrophin involved in learning and memory, the expression of which could be induced by circulating irisin, a peptide derived from Fibronectin type III domain-containing protein 5 (FNDC5) produced by skeletal muscle contraction. While the influence of EX modalities on cerebral BDNF expression was characterized, their effect on muscle FNDC5/Irisin expression and circulating irisin levels remains to be explored. The present study involved Wistar rats divided into four experimental groups: sedentary (SED), low- (40% of maximal aerobic speed, MAS), intermediate- (50% of MAS) and high- (70% of MAS) intensities of treadmill EX (30 min/day, 7 days). Soleus (SOL) versus gastrocnemius (GAS) FNDC5 and hippocampal BDNF expressions were evaluated by Western blotting. Additionally, muscular FNDC5/Irisin localization and serum/hippocampal irisin levels were studied by immunofluorescence and ELISA, respectively. Our findings revealed that (1) serum irisin and hippocampal BDNF levels vary with EX intensity, showing a threshold intensity at 50% of MAS; (2) hippocampal BDNF levels positively correlate with serum irisin but not with hippocampal FNDC5/Irisin; and (3) GAS, in response to EX intensity, overexpresses FNDC5/Irisin in type II muscle fibers. Altogether, peripheral FNDC5/Irisin levels likely explain EX-dependent hippocampal BDNF expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Fibronectinas , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fibronectinas/metabolismo , Ratos Wistar , Fatores de Transcrição/metabolismo , Músculo Esquelético/metabolismo
4.
Front Mol Neurosci ; 16: 1275924, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37868812

RESUMO

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain's response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.

5.
Stroke Vasc Neurol ; 2023 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-37429637

RESUMO

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.

6.
J Neurol Sci ; 448: 120611, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36958132

RESUMO

BACKGROUND: Identifying biological markers of ischemic stroke (IS) is an important research approach to develop innovative therapeutic strategies. This study aimed to assess the association between plasma Growth Differentiation Factor-8 (GDF-8)/Myostatin levels and outcome of IS patients. METHODS: Consecutive patients with acute IS treated with either intravenous thrombolysis and/or mechanical thrombectomy at Dijon University Hospital, France were prospectively included. Clinical variables were recorded, and plasma GDF-8 was collected just after the revascularization procedure. Primary endpoint was functional outcome at 3 months assessed by the modified Rankin Scale (mRS) score. Secondary endpoints included mRS scores at 6 and 12 months, and overall mortality over 1-year of follow-up. RESULTS: Among the 173 included patients (median age: 76 years, Interquartile range (IQR): 66-85; 49% women), median plasma GDF-8 levels at admission were significantly lower in those with a poor outcome at 3 months defined as a mRS score > 2 (2073 (IQR: 1564-2757) pg/mL versus 1471 (1192-2241) pg/mL, p < 0.001). Lower GDF-8 levels at admission were associated with higher 3-months mRS score in multivariable ordinal logistic regression analysis (OR = 0.9995; 95% CI: 0.9991-0.9999, p = 0.011). The association was also observed with 6- and 12-month mRS scores. Although mortality was higher in patients with lower GDF-8 levels, the association was not significant in multivariable Cox analysis. CONCLUSION: Lower plasma GDF-8 levels were associated with a poorer functional outcome in IS patients treated with acute revascularization therapy. Underlying pathophysiological mechanisms involving GDF-8 in post-stroke outcome remain to be elucidated.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Masculino , Prognóstico , Miostatina , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/cirurgia , Biomarcadores , Resultado do Tratamento , Isquemia Encefálica/cirurgia , Trombectomia/métodos
7.
Front Cardiovasc Med ; 9: 949213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911547

RESUMO

Background: 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/m2 [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. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03570060].

8.
J Clin Med ; 10(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34640343

RESUMO

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.

9.
Sci Rep ; 10(1): 16718, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028913

RESUMO

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-ß1, 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.


Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Macula Lutea/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Síndrome Coronariana Aguda/sangue , Idoso , Angiografia/métodos , Angiopoietina-2/sangue , Biomarcadores/sangue , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Macula Lutea/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/sangue , Fatores de Risco , Tomografia de Coerência Óptica/métodos , Fator de Crescimento Transformador beta1/sangue
10.
Arch Cardiovasc Dis ; 113(8-9): 564-571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32680738

RESUMO

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.


Assuntos
Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mitocôndrias/genética , Estresse Oxidativo , Transdução de Sinais , Regulação para Cima
11.
Molecules ; 25(10)2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32455902

RESUMO

The 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.


Assuntos
Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas Mitocondriais/genética , Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Transporte Biológico/genética , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Família Multigênica/genética , Neoplasias/terapia , Transportadores de Ânions Orgânicos/antagonistas & inibidores
12.
Int J Mol Sci ; 21(7)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283613

RESUMO

Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases.


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Fenômenos Fisiológicos da Pele , Pele/metabolismo , Animais , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Regeneração , Transdução de Sinais , Cicatrização/genética
13.
Biochim Biophys Acta Mol Basis Dis ; 1866(8): 165798, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32304740

RESUMO

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.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Fator 15 de Diferenciação de Crescimento/genética , Neoplasias/genética , Neovascularização Patológica/genética , Obesidade/genética , Microambiente Tumoral/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Inflamação , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Obesidade/metabolismo , Obesidade/patologia , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo
15.
Front Neurol ; 10: 611, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258506

RESUMO

Background and Aims: Growth differentiation factor-15 (GDF-15) has been identified as a robust marker of developing cardiovascular disease, however, little is currently known about its prognostic value in stroke patients. In a context of growing interest to discover new biomarkers in stroke, we aimed to assess the association between circulating GDF-15 levels and three-month mortality in ischemic stroke patients treated with acute revascularization therapy. Methods: 173 patients hospitalized for acute ischemic stroke and treated with either intravenous thrombolysis (n = 99, 57.2%), mechanical thrombectomy (n = 41, 23.4%) or combined therapy (n = 33, 19.1%) were prospectively included. Baseline clinical and biological characteristics were recorded. Plasma GDF-15 levels were measured at admission (D0), and at 24 h, 3 and 7 days. Clinical severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) score, and vital status was obtained 3 months after the stroke. Results: At 3 months post-stroke, 32 patients (18.5%) had died. The deceased patients had higher D0 plasma GDF-15 levels (median [IQR]: 2,777 [1,769-5,446] vs. 1,460 [965-2,079] pg/mL, P < 0.001). In multivariable logistic regression analysis, D0 GDF-15 levels in the third tertile of the distribution were independently associated with mortality at 3 months (OR = 3.71; 95% CI: 1.09-12.6, P = 0.036), even after adjustment for confounding variables including clinical severity. Conclusions: Our data show for the first time that GDF-15 plasma concentration at admission is independently associated with 3-month mortality in ischemic stroke patients treated with acute revascularization therapy. The pathophysiological mechanisms that could explain this association warrant further study.

16.
Calcif Tissue Int ; 105(3): 239-251, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31197415

RESUMO

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.


Assuntos
Osso e Ossos/metabolismo , Osteoporose/terapia , Osteoprotegerina/fisiologia , Terapias em Estudo/métodos , Calcificação Vascular/etiologia , Calcificação Vascular/terapia , Animais , Remodelação Óssea/fisiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Humanos , Osteoporose/etiologia , Transdução de Sinais/fisiologia , Terapias em Estudo/tendências , Calcificação Vascular/metabolismo
17.
Int J Mol Sci ; 20(3)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736365

RESUMO

The 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.


Assuntos
Vasos Sanguíneos/fisiologia , Endotélio/metabolismo , Ligantes , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Animais , Biomarcadores , Senescência Celular , Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Humanos , Miocárdio/metabolismo , Neovascularização Fisiológica , Osteoprotegerina/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Transporte Proteico , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
18.
J Clin Med ; 9(1)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31906236

RESUMO

OBJECTIVE: Growth differentiation factor-8 (GDF8), also known as myostatin, is a member of the transforming growth factor-ß superfamily that inhibits skeletal muscle growth. We aimed to investigate the association between GDF8 and peak troponin I levels after acute myocardial infarction (AMI). METHODS: All consecutive patients admitted from June 2016 to February 2018 for type 1 AMI in the Coronary Care Unit of University Hospital of Dijon Bourgogne (France) were included in our prospective study. Blood samples were harvested on admission, and serum levels of GDF8 were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: Among the 296 patients with type 1 AMI, median age was 68 years and 27% were women. GDF8 levels (median (IQR) = 2375 ng/L) were negatively correlated with age, sex and diabetes (p < 0.001 for all). GDF8 levels were higher in patients with in-hospital ventricular tachycardia or fibrillation (VT/VF) than those without in-hospital VT/VF. GDF8 was positively correlated with troponin I peak (r = 0.247; p < 0.001). In multivariate linear regression analysis, log GDF8 (OR: 21.59; 95% CI 34.08-119.05; p < 0.001) was an independent predictor of troponin I peak. CONCLUSIONS: These results suggest that GDF8 levels could reflect the extent of myocardial damage during AMI, similar to peak troponin I, which is currently used to estimate infarct size. Further studies are needed to elucidate the underlying mechanisms linking the GDF8 cytokine with troponin I levels.

19.
Int J Mol Sci ; 19(12)2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545044

RESUMO

Aging is a complicated pathophysiological process accompanied by a wide array of biological adaptations. The physiological deterioration correlates with the reduced regenerative capacity of tissues. The rejuvenation of tissue regeneration in aging organisms has also been observed after heterochronic parabiosis. With this model, it has been shown that exposure to young blood can rejuvenate the regenerative capacity of peripheral tissues and brain in aged animals. An endogenous compound called growth differentiation factor 11 (GDF11) is a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent cardiac diseases. The protein GDF11 is found in humans as well as animals. The existence of endogenous regulators of regenerative capacity, such as GDF11, in peripheral tissues and brain has now been demonstrated. It will be important to investigate the mechanisms with therapeutic promise that induce the regenerative effects of GDF11 for a variety of age-related diseases.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Fatores de Diferenciação de Crescimento/metabolismo , Regeneração , Sequência de Aminoácidos , Animais , Fatores de Diferenciação de Crescimento/química , Humanos , Parabiose
20.
Stroke ; 49(11): 2752-2760, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30355197

RESUMO

Background 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 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 2 hours, 24 hours, and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to ischemia-reperfusion injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LVs) were analyzed with Western blotting and quantitatve real-time polymerase chain reaction. 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 ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LV developed pressure and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 (growth differentiation factor 15) increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 (adrenoceptor ß1) and cardioprotective Survivor Activating Factor Enhancement signaling pathways. Conclusions- Our findings indicate that stroke not only impairs cardiac contractility but also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms of stroke-induced myocardial alterations after cerebral embolization remain to be established, insofar as they may involve the sympathetic nervous system and nitro-oxidative stress.


Assuntos
Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Suscetibilidade a Doenças , Ecocardiografia , Fator 15 de Diferenciação de Crescimento/sangue , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Preparação de Coração Isolado , Masculino , Isquemia Miocárdica/fisiopatologia , Estresse Nitrosativo , Estresse Oxidativo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 1/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia
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