New factors in heart failure pathophysiology : Immunity cells release of extracellular vesicles

Leukocyte-shed extracellular vesicles (EVs) can play effector roles in the pathophysiological mechanisms of different diseases. These EVs released by membrane budding of leukocytes have been found in high amounts locally in inflamed tissues and in the circulation, indicating immunity cell activation. These EVs secreted by immune cell subsets have been minimally explored and deserve further investigation in many areas of disease. In this study we have investigated whether in heart failure there is innate and adaptive immune cell release of EVs. Patients with chronic heart failure (cHF) (n = 119) and in sex- and age-matched controls without this chronic condition (n = 60). Specifically, EVs were quantified and phenotypically characterized by flow cytometry and cell-specific monoclonal antibodies. We observed that even in well medically controlled cHF patients (with guideline-directed medical therapy) there are higher number of blood annexin-V + (phosphatidylserine +)-EVs carrying activated immunity cell-epitopes in the circulation than in controls (p < 0.04 for all cell types). Particularly, EVs shed by monocytes and neutrophils (innate immunity) and by T-lymphocytes and natural-killer cells (adaptive immunity) are significantly higher in cHF patients. Additionally, EVs-shed by activated leukocytes/neutrophils (CD11b +, p = 0.006; CD29 + /CD15 +, p = 0.048), and T-lymphocytes (CD3 + /CD45 +, p < 0.02) were positively correlated with cHF disease severity (NYHA classification). Interestingly, cHF patients with ischemic etiology had the highest levels of EVs shed by lymphocytes and neutrophils (p < 0.045, all). In summary, in cHF patients there is a significant immune cell activation shown by high-release of EVs that is accentuated by clinical severity of cHF. These activated innate and adaptive immunity cell messengers may contribute by intercellular communication to the progression of the disease and to the common affectation of distant organs in heart failure (paracrine regulation) that contribute to the clinical deterioration of cHF patients

Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning

Altres ajuts: Ministerio de Ciencia e Innovación; Fundación de Investigación Cardiovascular-Fundación Jesús Serra.Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by postconditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria

Moderate beer intake downregulates inflammasome pathway gene expression in human macrophages

Inflammasomes are key components of the innate immunity system that trigger the inflammatory response. Inappropriate activity of the inflammasome system has been linked to onset and perpetuation of inflammation in atherosclerotic plaques and cardiovascular disease. Low-to-moderate beer consumption is inversely associated with cardiovascular event presentation, while high levels of alcohol intake are associated with increased cardiovascular risk. Although fermented beverages have been suggested to exert their beneficial effects through their anti-oxidant and anti-inflammatory properties, little is known regarding the capacity of beer to modulate innate immunity cell responses. To this aim, primed or activated THP-1 macrophages were conditioned with human serum obtained from a prospective two-arms longitudinal crossover study to investigate the effect of a moderate and regular daily intake of beer, either alcohol-free or traditional, in the regulation of TLR-mediated inflammatory responses in healthy but overweight individuals. Conditioned macrophages with serum obtained after four-week intervention with alcohol-free beer significantly reduced the transcription of pro-inflammatory interleukins such as IL-1β and TNF. The serum of traditional beer consumers did not exhibit the same capacity as the serum of alcohol-free beer consumers to reduce gene expression of pro-inflammatory interleukins; however, serum from traditional beer consumers showed a regulatory effect at the protein level by significantly decreasing the intracellular protein levels of pro-IL-1β in primed macrophages and preventing cleaved-IL-1β protein release

DJ-1 administration exerts cardioprotection in a mouse model of acute myocardial infarction.

Cardiovascular diseases, and particularly acute myocardial infarction (MI), are the most common causes of death worldwide. Infarct size is the major predictor of clinical outcomes in MI. The Parkinson's disease associated protein, DJ-1 (also known as PARK7), is a multifunctional protein with chaperone, redox sensing and mitochondrial homeostasis activities. Previously, we provided the evidence for a central role of endogenous DJ-1 in the cardioprotection of post-conditioning. In the present study, we tested the hypothesis that systemic administration of recombinant DJ-1 exerts cardioprotective effects in a mouse model of MI and also explored the associated transcriptional response. We report a significant treatment-induced reduction in infarct size, leukocyte infiltration, apoptosis and oxidative stress. Effects potentially mediated by G-protein-coupled receptor signaling and modulation of the immune response. Collectively, our results indicate a protective role for the exogenously administrated DJ-1 upon MI, and provide the first line of evidence for an extracellular activity of DJ-1 regulating cardiac injury in vivo.This work was supported by grants from: the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación SAF-2016-76819-R (to LB), MCIN/AEI/ 10.13039/501100011033, Plan Nacional Proyectos Investigación Desarrollo (PID 2019-107160RB-I00 to LB), and PGC 2018-094025-B-I00 (to GV); the Instituto de Salud Carlos III: CIBER-CV and ERA-CVD JTC 2020-023/AC 209-00054 (to LB) and FIS PI19/01687 (to TP). AG is a pre-doctoral fellow from BES-2017-081378. This article is part of AG PhD project at Universitat Autònoma de Barcelona (UAB).S

Understanding the long-term dynamics of forest transition: Fromdeforestation to afforestation in a Mediterranean landscape (Catalonia, 1868-2005)

As other Mediterranean areas, Catalonia has experienced a forest transition following rural abandonmentduring the last sixty years. The GIS reconstruction of three land-use maps of 1868, 1956 and 2005 showshow forests have encroached former cropland and pasture land from the 1950s onwards, after a previouswave of deforestation. Forest inventories reveal the overpressure exerted on woodlands up to the 1950s,and their poor ecological status in terms of age structure, diversity and maturity. They are prone to wild-fires, which in turn force a harvest of salvaged wood by a sudden forestry activity that entails a viciouscircle: the lack of a proper forest management increases wildfires, and leads to this sort of 'spasmodicforestry'. To overcome this situation, a sustainable forestry, combined with farming and extensive live-stock breeding are needed as a means to perform an active ecological restoration. Historical knowledgecan help in this task, by discovering the previous dynamics of current woodlands and providing a guid-ance to differentiate the scarce oldest forests from the ones that are younger as a result of the overuseexerted up to mid-20th century, and from many others that have regrown since the 1950s in abandonedsteep lands

Functional And Cognitive Decline Is Associated With Increased Endothelial Cell Inflammation And Platelet Activation. Liquid Biopsy Of Microvesicles In Community-Dwelling Octogenarians.

Increased life expectancy is usually associated with comorbidities, such as cardio andcerebrovascular disease causing impaired functionality. A common underlying cause ofthese comorbidities is vascular inflammation and injury. Elevated levels of circulatingmicrovesicles (cMV), as a product of a hemostatic and inflammatory cell activation,could be direct mapping of an imbalanced hemostasis. In this manuscript, we aimedto investigate by liquid biopsy whether successful aging can be discriminated bycMV levels and phenotype. To this purpose, we included 135 community-dwellingoctogenarians in a cross-sectional study. Successful aging was defined as goodfunctional (Barthel Index>90 points, and Lawton index score>7/4 points forwomen and men, respectively) and cognitive status (Spanish version of the Mini-Mental State Examination -MEC->24 points) and no need for institutionalization.Total, annexin V positive (AV+), and AV−cMV from different cell origins from thevascular compartment were phenotypically characterized and quantified from fastingplasma samples by flow cytometry. Successful aging was associated with lowerplasma concentrations of total and AV+CD141+/CD41+-CD61+, and PAC1+/AV+,CD141+/AV+, and CD36+/AV−cMV. From these phenotypes, ROC curve analysesrevealed that CD141+/AV+and CD141+/CD41+-CD61+/AV+endothelial- and platelet-derived cMV discriminate successful and non-successful aging with an AUC (95%CI) of0.655 (0.551, 0.758),P= 0.005, and 0.638 (0.535, 0.741),P= 0.013, respectively. In conclusion, successful aging is associated with low levels of cMV released by endothelialcells and platelets, indicating lower endothelial cell inflammation and platelet activation.Our results contribute to the understanding of the link between unsuccessful aging,cognitive decline and vascular cell inflammatory disturbances

Antiplatelet activity of isorhamnetin via mitochondrial regulation

Altres ajuts: Centro de Estudios en Alimentos Procesados-CEAP, ANID (National Doctorate Scholarship-Folio: 21191143, ANID R19A10001), Programa Regional R20F0001, Talca, Chile; CiberCV; Instituto Carlos III; Fundación de Investigación Cardiovascular-Fundación Jesús Serra, Spain.With the diet, we ingest nutrients capable of modulating platelet function, which plays a crucial role in developing cardiovascular events, one of the leading causes of mortality worldwide. Studies that demonstrate the antiplatelet and antithrombotic potential of bioactive compounds are vital to maintaining good cardiovascular health. In this work, we evaluate the flavonol isorhamnetin's antiplatelet effect on human platelets, using collagen, thrombin receptor activator peptide 6 (TRAP-6), and phorbol myristate acetate (PMA) as agonists. Isorhamnetin induced a significant inhibition on collagen-and TRAP-6-induced platelet aggregation, with half-maximum inhibitory concentration (IC) values of 8.1 ± 2.6 and 16.1 ± 11.1 µM, respectively; while it did not show cytotoxic effect. Isorhamnetin reduced adenosine triphosphate levels (ATP) in platelets stimulated by collagen and TRAP-6. We also evidenced that isorhamnetin's antiplatelet activity was related to the inhibition of mitochondrial function without effect on reactive oxygen species (ROS) levels. Additionally, we investigated isorhamnetin's effect on thrombus formation in vitro under flow conditions on the damaged vessel wall. In this context, we demonstrate that isorhamnetin at 20 µM induced a significant inhibition on platelet deposition, confirming its antithrombotic effect. Our findings corroborate the antiplatelet and antithrombotic potential of isorhamnetin present in many foods of daily consumption

A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients

Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients. This research was originally published in Lipid Research. A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients. Journal of Lipid Research. 2015. 56: 1762-1773 © the American Society for Biochemistry and Molecular Biology.Peer Reviewe

Towards an agroecological transition in the Mediterranean: A bioeconomic assessment of viticulture farming

Transformations in the agri-food system since the early 19th century have led to an unprecedented increase in food production. However, the structure of this system has generated many negative environmental and social impacts that threaten the sustainability at the local, regional and global scale. This situation entails the need for an agroecological transition that leads to an agri-food model that is aware of the planetary boundaries and guarantees the reproduction of human and all other forms of life. Agroecology is crucial for the Mediterranean, where the negative environmental and social impacts of industrial agriculture are particularly evident. The aim of this paper is to present a best practice viticulture farming that is in an advanced level of agroecological transition in the region. The results show that the energy efficiency of this agroecosystem is greater to conventional farms in the region, while generating similar financial returns but more equally distributed than the big agro-industrial companies in the sector. Based on this best practice case study, we provide several methodological and practical insights on the energy balance of the farm system, supplemented by data on the value-added distribution from wholesaler selling back to the industrial winemaking and vine-growing incomes, and the final financial returns of the company. The results highlight the need of multifactorial analyses that contribute to a systemic perspective on the synergic elements and leverage points for scaling-up the agroecological transition of Mediterranean viticulture

High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model

Altres ajuts: This work was supported by the Plan Nacional de Salud (PNS) from the Spanish Ministry of Science and Innovation and funds FEDER 'Una Manera de Hacer Europa'; a grant from the Spanish Society of Cardiology (Beca FEC Investigacio'n Ba'sica/2016 to G.V); the Instituto de Salud Carlos III (ISCIII); and CIBERCV (to L.B). We thank the support of the Generalitat of Catalunya (Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat,) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support.High-density lipoproteins (HDLs) are circulating micelles that transport proteins, lipids, and miRNAs. HDL-transported miRNAs (HDL-miRNAs) have lately received attention but their effects on vascular cells are not fully understood. Additionally, whether cardiovascular risk factors affect HDL-miRNAs levels and miRNA transfer to recipient cells remains equally poorly known. Here, we have investigated the changes induced by hypercholesterolaemia on HDL-miRNA levels and its effect on recipient endothelial cells (ECs). Pigs were kept on a high-fat diet (HC; n = 10) or a normocholesterolaemic chow (NC; n = 10) for 10 days reaching cholesterol levels of 321.0 (229.7-378.5) mg/dL and 74.0 (62.5-80.2) mg/dL, respectively. HDL particles were isolated, purified, and quantified. HDL-miRNA profiling (n = 149 miRNAs) of HC- and NC-HDLs was performed by multipanel qPCR. Cell cultures of porcine aortic ECs were used to determine whether HDL-miRNAs were delivered to ECs. Potential target genes modulated by miRNAs were identified by bioinformatics and candidate miRNAs were validated by molecular analysis. In vivo effects in the coronary arteries of normocholesterolaemic swine administered HC- or NC-HDLs were analysed. Among the HDL-miRNAs, four were found in different amounts in HC- and NC-HDL (P < 0.05). miR-126-5p and -3p and miR-30b-5p (2.7×, 1.7×, and 1.3×, respectively) were found in higher levels and miR-103a-3p and miR-let-7g-5p (−1.6×, −1.4×, respectively) in lower levels in HC-HDL. miR-126-5p and -3p were transferred from HC-HDL to EC (2.5×; P < 0.05), but not from NC-HDL, by a SRB1-mediated mechanism. Bioinformatics revealed that HIF1α was the miR-126 target gene with the highest predictive value, which was accordingly found to be markedly reduced in HC-HDL-treated ECs and in miR126 mimic transfected ECs. In vivo validation confirmed that HIF1α was diminished in the coronary endothelial layer of NC pigs administered HC-HDL vs. those administered NC-HDL (P < 0.05). Hypercholesterolaemia induces changes in the miRNA content of HDL enhancing miR126 and its delivery to ECs with the consequent down-regulation of its target gene HIF1α