Estudio del papel de la nesfatina-1 en el control de la viabilidad y el metabolismo cardiaco: implicaciones en la fisiopatología de las enfermedades cardiovasculares

La obesidad, condición que originó enormes esfuerzos de investigación en los últimos años sobre la fisiología del tejido adiposo, es un estado proinflamatorio claro en el que la hiperplasia e hipertrofia de las células grasas induce cambios severos en la secreción de adipocitoquinas, lo que en último término producirá cambios importantes en la sensibilidad a la insulina y la inflamación (Skurk et al. 2007). Hoy en día se cree que los individuos obesos se caracterizan por un estado proinflamatorio crónico que podría ser la causa del desarrollo de resistencia a la insulina y otros trastornos asociados con la obesidad, tales como la hiperlipidemia, el síndrome metabólico y la aterosclerosis (Lake et al. 2007). Las complicaciones cardiovasculares asociadas a la obesidad se conocen desde hace mucho tiempo, y la intensa investigación realizada en los últimos 20 años en relación con los productos de secreción de tejido adiposo nos permite empezar a comprender los vínculos entre la obesidad (obesidad especialmente visceral), el síndrome metabólico, procesos inflamatorios y las enfermedades cardiovasculares (Despres et al. 2006). La nesfatina es un nuevo péptido de 82 aminoácidos derivado de la proteína precursora Nucleobindin2 (NUCB2) (Oh et al. 2006). Este péptido, que está altamente conservado entre murinos y humanos, se expresa abundantemente en diversas regiones del hipotálamo, incluyendo el núcleo paraventricular (PVN), el núcleo supraóptico, el arcuatus, el núcleo lateral, y la zona incierta (Oh et al. 2006 , Brailoiuet. al 2007). La nesfatina se ha descrito como un nuevo péptido anorexigénico debido a su amplia distribución en las regiones del hipotálamo implicadas en la regulación del apetito y el metabolismo (Oh et al 2006;. Brailoiu et al 2007.) y a que su administración central suprime la ingesta (OHet al. 2006). En este proyecto nos propusimos: 1.-Determinar los efectos de la nesfatina sobre la viabilidad y el metabolismo energético de los cardiomiocitos. 2.- Estudiar sus niveles de expresión en el corazón ante distintas patologías cardiovasculares. 3.- Estudiar la posible existencia de mecanismos de regulación de tipo hormonal de manera autocrina/paracrina a nivel cardiomiocitario y el análisis de una posible síntesis y secreción de esta hormona por cardimiocitos. 4.- Estudiar la regulación de sus niveles de expresión cardiacos por la dieta, la lactancia materna y la obesidad inducida genéticamente. Con este trabajo hemos demostrado que los cardiomiocitos (murinos y humanos) son capaces de sintetizar y de secretar nesfatina-1; que la nesfatina-1 induce la captación de glucosa y de ácidos grasos por cardiomiocitos neonatales de rata en cultivo, así como la fosforilación de ERK1/2, AKT y AS160; que sus niveles de expresión génica a nivel cardiaco se ven influenciados por la dieta, la duración del periodo de lactancia y la edad; que la nesfatina-1 regula la viabilidad de cardiomiocitos murinos en cultivo; que los niveles de expresión génica de nesfatina-1 en tejido auricular cardiaco humano se ven modificados por el sexo, la presencia de enfermedad coronaria, el tratamiento con antidiabéticos orales y con antihipertensivos; que sus niveles de expresión génica en tejido ventricular son mayores en pacientes con cardiomiopatía isquémica en la fase final de la insuficiencia cardiaca; y, finalmente, que los niveles plasmáticos de nesfatina-1 están incrementados en pacientes con insuficiencia cardiaca que presentan reducción de la tolerancia al ejercicio

Injectable hybrid hydrogels physically crosslinked based on carrageenan and green graphene for tissue repair

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract] Injectable and biocompatible novel hybrid hydrogels based on physically crosslinked natural biopolymers and green graphene for potential use in tissue engineering are reported. Kappa and iota carrageenan, locust bean gum and gelatin are used as biopolymeric matrix. The effect of green graphene content on the swelling behavior, mechanical properties and biocompatibility of the hybrid hydrogels is investigated. The hybrid hydrogels present a porous network with three-dimensionally interconnected microstructures, with lower pore size than that of the hydrogel without graphene. The addition of graphene into the biopolymeric network improves the stability and the mechanical properties of the hydrogels in phosphate buffer saline solution at 37 °C without noticeable change in the injectability. The mechanical properties of the hybrid hydrogels were enhanced by varying the dosage of graphene between 0.025 and 0.075 w/v%. In this range, the hybrid hydrogels preserve their integrity during mechanical test and recover the initial shape after removing the applied stress. Meanwhile, hybrid hydrogels with graphene content of up to 0.05 w/v% exhibit good biocompatibility for 3T3-L1 fibroblasts; the cells proliferate inside the gel structure and show higher spreading after 48 h. These injectable hybrid hydrogels with graphene have promising future as materials for tissue repair.Xunta de Galicia; ED431C 2019/17Instituto de Salud Carlos III; CD21/00042Chile. CORFO; 22CVID-20683

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

Increased Expression of Fatty-Acid and Calcium Metabolism Genes in Failing Human Heart

Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca(2+))-handling in the human heart.RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left-ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6).Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca(2+)-handling genes (Two-Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5-triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca(2+)-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM.DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca(2+)-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca(2+)-handling genes

Adipokines and Inflammation: Focus on Cardiovascular Diseases

It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases

The pleiotropic hormone relaxin-2 plays a pivotal role in the physiology and pathology of the cardiovascular system. Relaxin-2 exerts relevant regulatory functions in cardiovascular tissues through the specific receptor relaxin family peptide receptor 1 (RXFP1) in the regulation of cardiac metabolism; the induction of vasodilatation; the reversion of fibrosis and hypertrophy; the reduction of inflammation, oxidative stress, and apoptosis; and the stimulation of angiogenesis, with inotropic and chronotropic effects as well. Recent preclinical and clinical outcomes have encouraged the potential use of relaxin-2 (or its recombinant form, known as serelaxin) as a therapeutic strategy during cardiac injury and/or in patients suffering from different cardiovascular disarrangements, especially heart failure. Furthermore, relaxin-2 has been proposed as a promising biomarker of cardiovascular health and disease. In this review, we emphasize the relevance of the endogenous hormone relaxin-2 as a useful diagnostic biomarker in different backgrounds of cardiovascular pathology, such as heart failure, atrial fibrillation, myocardial infarction, ischemic heart disease, aortic valve disease, hypertension, and atherosclerosis, which could be relevant in daily clinical practice and could contribute to comprehending the specific role of relaxin-2 in cardiovascular diseases

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

International audienceWe investigated whether the direct renin inhibitor aliskiren can affect metabolism in cardiomyocytes from rat, mouse and human sources. METHODS AND RESULTS: At 10-50μmol/L, aliskiren significantly increased medium-chain-fatty-acid uptake in primary-cultured neonatal-rat and HL-1 adult-mouse-derived cardiomyocytes (BODIPY-induced fluorescence intensity). The fatty-acid transporter CD-36 was correspondingly translocated to, but the glucose transporter Glut-4 away from, the sarcoplasmic reticulum/plasma membrane, in primary-cultured neonatal-rat (CD-36, Glut-4) and adult-human (CD-36) cardiomyocytes (confocal immunocytochemistry). Immunoblotting showed that aliskiren induced phosphorylation of ERK1/2 in cardiomyocytes from all three sources; responses were dose- and time-dependent, unaffected by renin treatment, and did not cause alterations in expression of (P)R or Igf2/M6P receptors. Microarray analysis of the complete genome of aliskiren-treated neonatal-rat cardiomyocytes, with RT-qPCR and immunoblot confirmation assays in rat and human primary cardiomyocytes, showed that aliskiren up-regulated mRNA and increased protein expression of several enzymes important in lipid and glucose metabolism and in cholesterol biosynthesis. Cardiomyocyte cell-cycle and viability were unaffected by aliskiren