BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery

Aims TGF-ß regulates tissue fibrosis: TGF-ß promotes fibrosis, whereas bone morphogenetic protein (BMP)-7 is antifibrotic. To demonstrate that (i) left ventricular (LV) remodelling after pressure overload is associated with disequilibrium in the signalling mediated by these cytokines, and (ii) BMP-7 exerts beneficial effects on LV remodelling and reverse remodelling. Methods and results We studied patients with aortic stenosis (AS) and mice subjected to transverse aortic constriction (TAC) and TAC release (de-TAC). LV morphology and function were assessed by echocardiography. LV biopsies were analysed by qPCR, immunoblotting, and histology. Pressure overload reduced BMP-7 and pSmad1/5/8 and increased TGF-ß and pSmad2/3 in AS patients and TAC mice. BMP-7 correlated inversely with collagen, fibronectin, and ß-MHC expressions, and with hypertrophy and diastolic dysfunction, and directly with the systolic function. Multiple linear regression disclosed BMP-7 and TGF-ß as hypertrophy predictors, negative and positive, respectively. BMP-7 prevented TGF-ß-elicited hypertrophic program in cardiomyocytes, and Col1A1 promoter activity in NIH-3T3 fibroblasts. The treatment of TAC mice with rBMP-7 attenuated the development of structural damage and dysfunction, and halted ongoing remodelling. The reverse remodelling after pressure overload release was facilitated by rBMP-7, and hampered by disrupting BMP-7 function using a neutralizing antibody or genetic deletion. Conclusion The disequilibrium between BMP-7 and TGF-ß signals plays a relevant role in the LV remodelling response to haemodynamic stress in TAC mice and AS patients. Our observations may provide new important insights aimed at developing novel therapies designed to prevent, halt, or reverse LV pathological remodelling in pressure overload cardiomyopathy

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

Pressure overload in patients with aortic stenosis (AS) induces an adverse remodeling of the left ventricle (LV) in a sex-specific manner. We assessed whether a sex-specific miR-29b dysregulation underlies this sex-biased remodeling pattern, as has been described in liver fibrosis. We studied mice with transverse aortic constriction (TAC) and patients with AS. miR-29b was determined in the LV (mice, patients) and plasma (patients). Expression of remodeling-related markers and histological fibrosis were determined in mouse LV. Echocardiographic morpho-functional parameters were evaluated at baseline and post-TAC in mice, and preoperatively and 1 year after aortic valve replacement (AVR) in patients with AS. In mice, miR-29b LV regulation was opposite in TAC-males (down-regulation) and TAC-females (up-regulation). The subsequent changes in miR-29b targets (collagens and GSK-3?) revealed a remodeling pattern that was more fibrotic in males but more hypertrophic in females. Both systolic and diastolic cardiac functions deteriorated more in TAC-females, thus suggesting a detrimental role of miR-29b in females, but was protective in the LV under pressure overload in males. Clinically, miR-29b in controls and patients with AS reproduced most of the sexually dimorphic features observed in mice. In women with AS, the preoperative plasma expression of miR-29b paralleled the severity of hypertrophy and was a significant negative predictor of reverse remodeling after AVR; therefore, it may have potential value as a prognostic biomarker

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), the European Regional D evelopment Fund, and the European Commission through H2020-EU.1.1, European Research Council grant ERC-2016-StG 715322-EndoMitTalk, and Gobierno de Espana SAF2016-80305P. This work was partially supported by Comunidad de Madrid (S2017/BMD 3867 RENIM-CM) and cofinanced by the European Structural and Investment Fund. M.M. is supported by the Miguel Servet Program (CP 19/014, Fundacion de Investigacion del Hospital 12 de Octubr

Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion

Aims Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway. PMCA4 activity is inhibited by the small molecule aurintricarboxylic acid (ATA). We hypothesize that inhibition of PMCA4 with ATA might enhance VEGF-induced angiogenesis. Methods and results We show that inhibition of PMCA4 with ATA in endothelial cells triggers a marked increase in VEGF-activated calcineurin/NFAT signalling that translates into a strong increase in endothelial cell motility and blood vessel formation. ATA enhances VEGF-induced calcineurin signalling by disrupting the interaction between PMCA4 and calcineurin at the endothelial-cell membrane. ATA concentrations at the nanomolar range, that efficiently inhibit PMCA4, had no deleterious effect on endothelial-cell viability or zebrafish embryonic development. However, high ATA concentrations at the micromolar level impaired endothelial cell viability and tubular morphogenesis, and were associated with toxicity in zebrafish embryos. In mice undergoing experimentally-induced hindlimb ischaemia, ATA treatment significantly increased the reperfusion of post-ischaemic limbs. Conclusions Our study provides evidence for the therapeutic potential of targeting PMCA4 to improve VEGF-based pro-angiogenic interventions. This goal will require the development of refined, highly selective versions of ATA, or the identification of novel PMCA4 inhibitors

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.</jats:p

Co-option of Neutrophil Fates by Tissue Environments.

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.This study was supported byIntramural grants from the Severo Ochoa program (IGP-SO), a grant from Fundacio la Marato de TV3 (120/C/2015-20153032), grant SAF2015-65607-R fromMinisterio de Ciencia e Innovacion (MICINN) with co-funding by Fondo Eu-ropeo de Desarrollo Regional (FEDER), RTI2018-095497-B-I00 from MICINN,HR17_00527 from Fundacion La Caixa, and Transatlantic Network of Excel-lence (TNE-18CVD04) from the Leducq Foundation to A.H. I.B. is supportedby fellowship MSCA-IF-EF-748381 and EMBO short-term fellowship 8261.A.R.-P. is supported by a fellowship (BES-2016-076635) and J.A.N.-A. byfellowship SVP-2014-068595 from MICINN. R.O. is supported by ERC startinggrant 759532, Italian Telethon Foundation SR-Tiget grant award F04, ItalianMoH grant GR-201602362156, AIRC MFAG 20247, Cariplo Foundation grant2015-0990, and the EU Infect-ERA 126. C.S. is supported by the SFB 1123,project A07, as well as by the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research) grant81Z0600204. L.G.N. is supported by SIgN core funding from A*STAR. The CNIC is supported by the MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505). G.F.-C. issupported by the Spanish Ministerio de Ciencia e Innovacio ́n (grantPID2019-110895RB-100) and Junta de Comunidades de Castilla-La Mancha(grant SBPLY/19/180501/000211). C.R. received funding from the BoehingerIngelheim Foundation (consortium grant ‘‘Novel and Neglected CardiovascularRisk Factors’’) and German Federal Ministry of Education and Research(BMBF 01EO1503) and is a Fellow of the Gutenberg Research College (GFK)at the Johannes Gutenberg-University MainzS

Aneurismas de la aorta toracoabdominal: guías de indicación quirúrgica y manejo intra y postoperatorio

Los aneurismas de la aorta toracoabdominal representan, aún hoy, uno de los verdaderos desafíos a los que el cirujano cardiovascular debe enfrentarse. La magnitud de la empresa que supone su tratamiento procede, por una parte, del pronóstico infausto de la historia natural de esta entidad en ausencia de tratamiento quirúrgico y, por otra, de las graves complicaciones potenciales asociadas a la cirugía. La combinación de: invasión de las cavidades torácica y abdominal, uso de ventilación unipulmonar, pérdida hemática masiva, sobrecarga cardíaca e interferencia con la perfusión de la médula espinal, riñones, resto de vísceras abdominales y extremidades inferiores, así como el grado avanzado de aterosclerosis que presenta la mayor parte de estos pacientes, explica la morbimortalidad asociada al tratamiento de esta enfermedad y justifica la logística cuasi militar que su cirugía requiere. En este escenario de afectación multisistema y de riesgo de complicación múltiple, la consecución de resultados quirúrgicos adecuados exige un abordaje multidisciplinar en el que el cirujano debe cooperar estrechamente con anestesiólogos, perfusionistas, intensivistas y clínicos. Es imprescindible insistir, además, en la necesidad de concentrar esta enfermedad en unos pocos centros de referencia quirúrgicos, ya que la calidad de resultados en este campo está en relación directa con las casuísticas, tanto del hospital como del cirujano. El presente documento contiene información resumida y actualizada acerca de las características clínicas y anatómicas de los aneurismas toracoabdominales, su historia natural, indicaciones quirúrgicas y manejo pre, intra y postoperatorio, prestando atención especial a aquellos aspectos relacionados con el desarrollo de complicaciones postoperatorias

Maria Lluïsa Serra Bellabre, bibliotecària, arxivera i directora de la Casa de Cultura de Maó

Aquest escrit tractarà de destacar l’aportació de Maria Lluïsa Serra al pano- rama bibliotecari de la seva època, un aspecte desconegut si el comparam amb el reconeixement general dels treballs d’investigació arqueològica que realitzà i que evidenciaren l’aportació menorquina a la cultura prehistòrica i protohis- tòrica de la Mediterrània.Hi ha un abans i un després a la història de la Biblioteca Pública en els tres quinquennis que exercí la seva direcció. Tractarem de veure l’evolució d’aquest centre dins un context més general, per poder apreciar els valors que el seu treball pogué afegir al context bibliotecari de l’època.Així com en el camp de l’arqueologia la nostra directora sabé trobar mentors de reconegut prestigi per desenvolupar els projectes en què treballava, en el camp bibliotecari, el seu paisà Francisco Sintes Obrador, llavors director gene- ral d’Arxius i Biblioteques, va trobar en ella una decidida col·laboradora amb la política que impulsava.

Protocolo de actuación inicial en la disección aórtica aguda

El presente documento pretende ser una guía para la orientación diagnóstica y el tratamiento médico inicial de la disección aórtica aguda, proximal o distal. Esta entidad constituye una complicación catastrófica de la enfermedad aórtica, con consecuencias a menudo fatales, y cuyo abordaje exige procedimientos diagnósticos y de tratamiento medicoquirúrgico que, con frecuencia, se llevarán a cabo fuera de la jornada de trabajo habitual y, en ocasiones, por personal con experiencia insuficiente. Estas circunstancias obligan, por una parte, a ser flexibles y adaptarse a las condiciones locales a la hora de planear la estrategia diagnóstica y de tratamiento y, por otra, reiteran la importancia de la existencia de guías de actuación que faciliten un abordaje estandarizado del problema. No pretendemos hacer una revisión exhaustiva del tema, pues el objetivo es dar pautas de manejo a personal con formación completa. Tampoco entramos en la descripción o discusión de las diferentes técnicas quirúrgicas aplicables en la disección aórtica, pues entendemos que esto excedería el objetivo inicial del documento y, además, invadiría el margen de actuación del cirujano, que deberá estar condicionado por su propio entrenamiento y experiencia clínica personal

Hallazgos anatomopatológicos en zorros (Vulpes vulpes) de Castilla y León

Trabajo presentado a la XXI Reunión de la Sociedad Española de Anatomía Patológica Veterinaria (SEAPV). ( Ferreira de Pantón, Lugo. 24-26 de junio de 2009). .Un total de 55 zorros rojos (Vulpes vulpes), procedentes de un programa de evaluación de trampas, fueron remitidos al Servicio de Diagnóstico Anatomopatológico de la Universidad de León. Los animales procedían de las provincias de León, Segovia y Soria. Además de las lesiones específicas ocasionadas por los diferentes modelos de trampas, se observaron otras patologías: granulomas parasitarios por migración errática de larvas de ascáridos en riñones de 28 animales, en pulmón de otros 2 casos y en miocardio en uno; nódulos de espirocercosis en el estómago de 16 zorros así como presencia de formas adultas de parásitos intestinales (en 17 casos nematodos y en 15 cestodos). En 7 animales se detectaron quistes de sarcosporidios en músculo esquelético, presentando uno de ellos además larvas de Trichinella spp. Dos animales mostraban un avanzado estado de caquexia, en uno de ellos asociado a una dermatitis parasitaria grave por Sarcoptes scabiei. Otras lesiones observadas fueron: túbulonefrosis entre leve y moderada, en un total de 46 animales y nefrosis pigmentaria en 31 de estos casos, así como neumonía catarral leve en 2 animales. No se detectaron lesiones musculares graves que pudieran asociarse a estrés de captura, si bien en un caso se observó una miopatía degenerativa focal posiblemente relacionada con un traumatismo moderado.Peer reviewe