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1.
Cells ; 9(3)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32111102

RESUMO

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of 'hidden cardiotoxicity' is defined as cardiotoxicity of a drug that manifests in the diseased (e.g. ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g. ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.

2.
Br J Pharmacol ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059259

RESUMO

During the last decades, mortality from acute myocardial infarction has been dramatically reduced. However, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischaemic conditioning had been discovered more than three decades ago. Its clinical translation, however, is still an unmet need. This is mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors, co-morbidities and the medication being taken. Sensory neuropathy is one of the co-morbidities that has been shown to interfere with cardioprotection. In the present review, we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which these neuropathies may interfere with ischaemic heart disease and cardioprotective signalling. Finally, we suggest future therapeutic options targeting both ischaemic heart and sensory neuropathy simultaneously.

3.
Br J Pharmacol ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31976545

RESUMO

Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies.

4.
J Cell Mol Med ; 24(5): 2857-2865, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31970899

RESUMO

Increased stiffness characterizes the early change in the arterial wall with subclinical atherosclerosis. Proteins inducing arterial stiffness in diabetes and hypercholesterolaemia are largely unknown. This study aimed at determining the pattern of protein expression in stiffening aorta of diabetic and hypercholesterolaemic mice. Male Ins2+/Akita mice were crossbred with ApoE-/- (Ins2+/Akita : ApoE-/- ) mice. Relative aortic distension (relD) values were determined by ultrasound analysis and arterial stiffness modulators by immunoblotting. Compared with age- and sex-matched C57/BL6 control mice, the aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed increased aortic stiffness. The aortas of Ins2+/Akita , ApoE-/- and Ins2+/Akita :ApoE-/- mice showed greater expression of VCAM-1, collagen type III, NADPH oxidase and iNOS, as well as reduced elastin, with increased collagen type III-to-elastin ratio. The aorta of Ins2+/Akita and Ins2+/Akita :ApoE-/- mice showed higher expression of eNOS and cytoskeletal remodelling proteins, such as F-actin and α-smooth muscle actin, in addition to increased glycosylated aquaporin (AQP)-1 and transcription factor NFAT5, which control the expression of genes activated by high glucose-induced hyperosmotic stress. Diabetic and hypercholesterolaemic mice have increased aortic stiffness. The association of AQP1 and NFAT5 co-expression with aortic stiffness in diabetes and hypercholesterolaemia may represent a novel molecular pathway or therapeutic target.

5.
Pharmacol Res ; 151: 104578, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794870

RESUMO

AIM: Acute myocardial infarction and subsequent post-infarction heart failure are among the leading causes of mortality worldwide. The endocannabinoid system has emerged as an important modulator of cardiovascular disease, however the role of endocannabinoid metabolic enzymes in heart failure is still elusive. Herein, we investigated the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. METHODS AND RESULTS: Quantitative real-time PCR, targeted lipidomics, and activity-based protein profiling (ABPP) enabled assessment of the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. Based on lipidomic analysis, two subgroups were identified within the ischemic heart failure group; the first similar to control hearts and the second with decreased levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and drastically increased levels of the endocannabinoid anandamide (AEA), other N-acylethanolamines (NAEs) and free fatty acids. The altered lipid profile was accompanied by strong reductions in the activity of 13 hydrolases, including the 2-AG hydrolytic enzyme monoacylglycerol lipase (MGLL). CONCLUSIONS: Our findings suggest the presence of different biological states within the ischemic heart failure group, based on alterations in the lipid and hydrolase activity profiles. In addition, this study demonstrates that ABPP is a valuable tool to rapidly analyze enzyme activity in clinical samples with potential for novel drug and biomarker discovery.

6.
Eur J Pharmacol ; 868: 172793, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31743738

RESUMO

In memoriam of Joseph Knoll: the selegiline story continues.

7.
Br J Pharmacol ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769007

RESUMO

Hyperlipidaemia is a well-established risk factor for cardiovascular diseases and therefore, many animal model have been developed to mimic the human abnormal elevation of blood lipid levels. In parallel, extensive research for the alleviation of ischaemia/reperfusion injury has revealed that hyperlipidaemia is a major co-morbidity that attenuates the cardioprotective effect of conditioning strategies (preconditioning, postconditioning and remote conditioning) and that of pharmacological interventions by interfering with cardioprotective signalling pathways. In the present review article, we summarize the existing data on animal models of hypercholesterolaemia (total, low density and HDL abnormalities) and hypertriglyceridaemia used in ischaemia/reperfusion injury and protection from it. We also provide recommendations on preclinical animal models to be used for translations of the cardioprotective strategies into clinical practice.

8.
Int J Mol Sci ; 20(17)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480394

RESUMO

Feeding rats with high-fat diet (HFD) with a single streptozotocin (STZ) injection induced obesity, slightly elevated fasting blood glucose and impaired glucose and insulin tolerance, and caused cardiac hypertrophy and mild diastolic dysfunction as published before by Koncsos et al. in 2016. Here we aimed to explore the renal consequences in the same groups of rats. Male Long-Evans rats were fed normal chow (CON; n = 9) or HFD containing 40% lard and were administered STZ at 20 mg/kg (i.p.) at week four (prediabetic rats, PRED, n = 9). At week 21 blood and urine samples were taken and kidney and liver samples were collected for histology, immunohistochemistry and for analysis of gene expression. HFD and STZ increased body weight and visceral adiposity and plasma leptin concentration. Despite hyperleptinemia, plasma C-reactive protein concentration decreased in PRED rats. Immunohistochemistry revealed elevated collagen IV protein expression in the glomeruli, and Lcn2 mRNA expression increased, while Il-1ß mRNA expression decreased in both the renal cortex and medulla in PRED vs. CON rats. Kidney histology, urinary protein excretion, plasma creatinine, glomerular Feret diameter, desmin protein expression, and cortical and medullary mRNA expression of TGF-ß1, Nrf2, and PPARγ were similar in CON and PRED rats. Reduced AMPKα phosphorylation of the autophagy regulator Akt was the first sign of liver damage, while plasma lipid and liver enzyme concentrations were similar. In conclusion, glomerular collagen deposition and increased lipocalin-2 expression were the early signs of kidney injury, while most biomarkers of inflammation, oxidative stress and fibrosis were negative in the kidneys of obese, prediabetic rats with mild heart and liver injury.


Assuntos
Colágeno/metabolismo , Glomérulos Renais/lesões , Glomérulos Renais/metabolismo , Lipocalina-2/metabolismo , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Tecido Adiposo/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal , Dieta Hiperlipídica , Fibrose , Regulação da Expressão Gênica , Inflamação/genética , Inflamação/patologia , Glomérulos Renais/patologia , Lipídeos/sangue , Fígado/enzimologia , Fígado/patologia , Fígado/fisiopatologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/sangue , Estresse Oxidativo/genética , Fosforilação , Fosfosserina/metabolismo , Estado Pré-Diabético/sangue , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Long-Evans , Estreptozocina
9.
Biomolecules ; 9(9)2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509973

RESUMO

AIM: We aimed to examine the alterations of the insulin signaling pathway, autophagy, nitrative stress and the effect of vitamin D supplementation in the liver and ovaries of vitamin D deficient hyperandrogenic rats. METHODS: Female Wistar rats received eight weeks of transdermal testosterone treatment and lived on a low vitamin D diet (D-T+). Vitamin D supplementation was achieved by oral administration of vitamin D3 (D+T+). Sham-treated (D+T-) and vitamin D deficient animals (D-T-) served as controls. (N = 10-12 per group). RESULTS: D-T+ animals showed decreased LC3 II levels in the liver and increased p-Akt/Akt and p-eNOS/eNOS ratios with decreased insulin receptor staining in the ovaries. Vitamin D supplementation prevented the increase of Akt phosphorylation in the ovaries. Vitamin D deficiency itself also led to decreased LC3 II levels in the liver and decreased insulin receptor staining in the ovaries. D-T+ group showed no increase in nitrotyrosine staining; however, the ovaries of D-T- rats and the liver of D+T+ animals showed increased staining intensity. CONCLUSION: Vitamin D deficiency itself might lead to disrupted ovarian maturation and autophagy malfunction in the liver. Preventing Akt phosphorylation may contribute to the beneficial effect of vitamin D treatment on ovarian function in hyperandrogenism.

10.
Front Physiol ; 10: 889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354526

RESUMO

Background: Recent evidences suggest that sex hormones may be involved in the regulation of exercise-induced left ventricular (LV) hypertrophy. However, the sex-specific functional consequences of exercise-induced myocardial hypertrophy is still not investigated in detail. We aimed at understanding the sex-specific functional and morphological alterations in the LV and the underlying molecular changes in a rat model of athlete's heart. Methods: We divided our young, adult male and female rats into control and exercised groups. Athlete's heart was induced by a 12-week long swim training. Following the training period, we assessed LV hypertrophy with echocardiography, while pressure-volume analysis was performed to investigate in vivo LV function. After in vivo experiments, molecular biological studies and histological investigations were performed. Results: Echocardiography and post-mortem measured heart weight data indicated LV hypertrophy in both genders, nevertheless it was more pronounced in females. Despite the more significant relative hypertrophy in females, characteristic functional parameters did not show notable differences between the genders. LV pressure-volume analysis showed increased stroke volume, improved contractility and stroke work and unaltered LV stiffness in both male and female exercised rats, while active relaxation was ameliorated solely in male animals. The induction of Akt signaling was more significant in females compared to males. There was also a characteristic difference in the mitogen-activated protein kinase pathway as suppressed phosphorylation of p44/42 MAPK (Erk) and mTOR was observed in female exercised rats, but not in male ones. Myosin heavy chain α (MHC)/ß-MHC ratio did not differ in males, but increased markedly in females. Conclusion: Our results confirm that there is a more pronounced exercise-induced LV hypertrophy in females as compared to the males, however, there are only minor differences regarding LV function. There are characteristic molecular differences between male and female animals, that can explain different degrees of LV hypertrophy.

11.
Mol Cell Biochem ; 460(1-2): 195-203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280435

RESUMO

L-Alpha-glycerylphosphorylcholine (GPC) is a widely used food supplement. GPC has been shown to exert beneficial effects in several organs; however, the cardiac effects of GPC have yet to be investigated. The aim of the present study was therefore to map out the effects of GPC on cardiac myocytes, with or without ischemia-reperfusion insult. Neonatal rat cardiac myocytes were treated with GPC at 1, 10, 80, and 100 µM concentrations for 15 min, 3 h, or 24 h, respectively. Cell viability by calcein assay and the degree of oxidative stress by DHE (superoxide level) and H2DCF (total ROS accumulation) staining were measured. In separate experiments, cardiomyocytes were pre-treated with the optimal concentration of GPC for 3 h and then cells were exposed to 4 h of simulated ischemia followed by 2 h of reperfusion (SI/R). Cell viability was measured at the end of the SI/R protocol. In normoxic conditions, the 15-min and the 3-h GPC treatment did not affect cell viability, total ROS, and superoxide levels. Under SI/R conditions, the 3-h GPC treatment protected the cardiac myocytes from SI/R-induced cell death and did not alter the level of oxidative stress. The 24-h GPC treatment in normoxic conditions resulted in significant cell death and increased oxidative stress at each concentration. Here we provide the first evidence for the cytoprotective effect of short-term GPC treatment. However, long-term administration of GPC may exert cytotoxicity in a wide concentration range in cardiac myocytes. These results may draw attention to a comprehensive cardiac safety protocol for the testing of GPC.


Assuntos
Citoproteção/efeitos dos fármacos , Glicerilfosforilcolina/farmacologia , Miócitos Cardíacos/citologia , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glicerilfosforilcolina/administração & dosagem , Glicerilfosforilcolina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos Wistar
12.
J Mol Cell Cardiol ; 131: 171-186, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055035

RESUMO

RATIONALE: Understanding mechanisms of the therapeutic effects of stem/progenitor cells, among which adipose tissue-derived mesenchymal stromal cells (AT-MSCs), has important implications for clinical use. Since the majority of such cells die within days or weeks after transplantation and do not persist in the transplanted organ or tissue, their effects appear to be largely mediated by paracrine signaling pathways, and are enhanced by overexpression of the antisenescent protein telomerase reverse transcriptase (TERT), and the anti-apoptotic transcription factor myocardin (MYOCD). AIM: By a proteomic approach combining two-dimensional gel electrophoresis (2DE) with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF/TOF) mass spectrometry, we aimed at analyzing how soluble and vesicular secretomes of aged murine AT-MSCs and their angiogenic function are modulated by the overexpression of TERT and MYOCD. METHODS: We cultured murine mock-transduced AT-MSCs and "rejuvenated" AT-MSCs overexpressing TERT and MYOCD (rTMAT-MSCs) harvested from 1-year-old male C57BL/6 mice. We established proteomes from 3 mock-transduced AT-MSCs and rTMAT-MSCs cultures in serum-free conditions, as well as their corresponding conditioned medium (CM) and exosome-enriched fractions (Exo+). RESULTS AND CONCLUSIONS: Proteomic analysis revealed a 2-fold increase of matrix metalloproteinase-2 (MMP-2) and its inhibitor metalloproteinase inhibitor 2 (TIMP2) in the CM - but not in the Exo + - of rTMAT-MSCs as compared to mock-transduced AT-MSCs. At the functional level, rTMAT-MSCs-CM, and - to a lesser extent - its Exo + fraction, increased tube formation of human vein endothelial cells (HUVECs), which could be blocked by anti-MMP2 and enhanced by anti-TIMP2 antibodies, respectively. Altogether, our results identify MMP2 and its inhibitor TIMP2 as novel candidates by which rTMAT-MSCs can support angiogenesis. Our strategy also illustrates the usefulness of comparative targeted proteomic approach to decipher molecular pathways underlying rTMAT-MSCs properties.

13.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052231

RESUMO

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.


Assuntos
Exossomos/metabolismo , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Fibrilação Ventricular/metabolismo , Animais , Feminino , Ventrículos do Coração/metabolismo , MicroRNAs/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Suínos , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/terapia , Função Ventricular
14.
Front Pharmacol ; 10: 233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949048

RESUMO

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully understood. Therefore, we investigated the role of MMPs in the K/BxN serum-transfer model of RA with the broad-spectrum MMP inhibitor subantimicrobial dose doxycycline (SDD) using complex in vivo and in vitro methodolgy. Methods: Chronic arthritis was induced by repetitive i.p. injections of K/BxN serum in C57BL/6J mice. SDD was administered daily in acidified drinking water (0.5 mg/mL, 80 mg/kg) during the 30 days experimental period. Mechanonociceptive threshold of the paw was evaluated by aesthesiometry, grasping ability by grid test, arthritis severity by scoring, neutrophil myeloperoxidase activity by luminescence, vascular hyperpermeability and MMP activity by fluorescence in vivo imaging and the latter also by gelatin zymography, bone structure by micro-computed tomography (micro-CT). Plasma concentrations of doxycycline were determined by liquid chromatography-mass spectrometry analysis. Results: K/BxN serum induced significant inflammatory signs, mechanical hyperalgesia, joint function impairment, increased myeloperoxidase activity and vascular hyperpermeability. Significant increase of MMP activity was also observed both in vivo and ex vivo with elevation of the 57-60, 75, and 92 kDa gelatinolytic isoforms in the arthritic ankle joints, but neither MMP activity nor any above described functional parameters were influenced by SDD. Most importantly, SDD significantly reduced bone mineral density in the distal tibia and enhanced the Euler number in the ankle. Arthritis-induced microarchitectural alterations demonstrating increased irregularity and cancellous bone remodeling, such as increased Euler number was significantly elevated by SDD in both regions. Conclusion: We showed increase of various MMP activities in the joints by in vivo fluorescence imaging together with ex vivo zymography, and investigated their functional significance using the broad-spectrum MMP inhibitor SDD in the translational RA model. This is the first demonstration that SDD worsens arthritis-induced bone microarchitectural alterations, but it appears to be independent of MMP inhibition.

15.
Bioinformatics ; 35(21): 4490-4492, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004478

RESUMO

MOTIVATION: Network visualizations of complex biological datasets usually result in 'hairball' images, which do not discriminate network modules. RESULTS: We present the EntOptLayout Cytoscape plug-in based on a recently developed network representation theory. The plug-in provides an efficient visualization of network modules, which represent major protein complexes in protein-protein interaction and signalling networks. Importantly, the tool gives a quality score of the network visualization by calculating the information loss between the input data and the visual representation showing a 3- to 25-fold improvement over conventional methods. AVAILABILITY AND IMPLEMENTATION: The plug-in (running on Windows, Linux, or Mac OS) and its tutorial (both in written and video forms) can be downloaded freely under the terms of the MIT license from: http://apps.cytoscape.org/apps/entoptlayout. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

16.
Noncoding RNA ; 5(2)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934986

RESUMO

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

17.
Circ Res ; 124(6): 938-951, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30870121

RESUMO

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .


Assuntos
Miócitos Cardíacos/fisiologia , Regeneração/fisiologia , Medicina Regenerativa , Fibroblastos/fisiologia , Humanos , Inflamação/fisiopatologia
18.
Cells ; 8(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884758

RESUMO

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Disbiose/patologia , Intestino Delgado/enzimologia , Intestino Delgado/patologia , Lactonas/farmacologia , Sulfonas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Celecoxib/farmacologia , Dinoprostona/biossíntese , Disbiose/microbiologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos Wistar , Fatores de Tempo
19.
Int J Mol Sci ; 20(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823517

RESUMO

BACKGROUND: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. METHODS: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. RESULTS: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. CONCLUSION: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.


Assuntos
Insuficiência Cardíaca Diastólica/etiologia , MicroRNAs/genética , Polineuropatias/complicações , Animais , Capsaicina/toxicidade , Modelos Animais de Doenças , Fator de Iniciação 4E em Eucariotos/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Proteínas Facilitadoras de Transporte de Glucose/genética , Insuficiência Cardíaca Diastólica/genética , Fator de Crescimento Insulin-Like I/genética , Masculino , Polineuropatias/induzido quimicamente , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Wistar
20.
Cardiovasc Res ; 115(7): 1167-1177, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796814

RESUMO

Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

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