Regulación de la viabilidad y el metabolismo cardiomiocitario por fármacos (aliskiren) y hormonas (chemerina) con capacidad de modular procesos inflamatorios

DocuRegulación de la viabilidad y el metabolismo cardiomiocitario por fármacos (aliskiren) y hormonas (chemerina) con capacidad de modular procesos inflamatorios. La obesidad se ha convertido en las últimas décadas en una de las principales causas de muerte y discapacidad, pasando a considerarse un grave problema de salud pública debido a su fuerte asociación con una elevada morbimortalidad por patologías tales como la diabetes mellitus tipo II, enfermedades cardiovasculares, accidentes cerebrovasculares, ateroesclerosis, hipertensión arterial, hiperlipemias, osteoartritis y algunos tipos de cáncer (Rega-Kaun G. et al, 2013). En la obesidad se produce una disfunción de las células adiposas que conlleva a un desequilibrio en los productos secretados por el tejido adiposo como las adipocitoquinas y otros factores que, a su vez, inducen un estado proinflamatorio sistémico (Skurk et al. 2007). Las adipocitoquinas participan en la regulación de la homeostasis a nivel sistémico mediante mecanismos endocrinos, paracrinos y autocrinos y el desequilibrio en su producción contribuye al desarrollo de enfermedades cardiovasculares y otros desórdenes como la resistencia a la insulina, la hipertensión, la ateroesclerosis y el síndrome metabólico (Rosen et al, 2006) (Lago F. et al, 2007). La acumulación crónica de grasa produce una serie de adaptaciones a nivel cardiovascular con el objetivo de mantener la homeostasis corporal (Bastien M. et al, 2014). En pacientes obesos el gasto cardíaco se incrementa debido al aumento del volumen de sangre circulante que debe satisfacer las necesidades metabólicas en estos estados (Bastien M. et al, 2014). A largo plazo, el aumento de volumen sanguíneo incrementa la tensión en la pared ventricular y conducirá a la aparición de la hipertrofia ventricular, la degeneración a nivel muscular, el incremento del volumen sanguíneo y las disfunciones sistólica y diastólica son los principales precursores de la insuficiencia cardiaca en la obesidad (Poirier P. et al, 2006). Adicionalmente, la existencia de diferentes comorbilidades asociadas con la obesidad pueden predisponer a los pacientes obesos a padecer hipertensión o diabetes de tipo II (Poirier P. et al, 2006). La combinación de la obesidad y la hipertensión tiene dos consecuencias importantes. En primer lugar, esta combinación es particularmente insidiosa debido a que la población con obesidad e hipertensión tienen una alta morbilidad y mortalidad por enfermedades cardiovasculares, incluyendo la enfermedad coronaria, insuficiencia cardíaca congestiva, muerte súbita cardiaca, enfermedad renal crónica, enfermedad renal terminal y accidentes cerebrovasculares (Landsberg L. et al, 2013). En segundo lugar, la obesidad aumenta el riesgo de desarrollar hipertensión arterial resistente al tratamiento por lo que estos pacientes requieren de uno o más fármacos antihipertensivos (Jordan J. et al, 2012). El aliskiren fue el primer inhibidor oral de la renina aprobado para combatir la hipertensión. Además de su efecto antihipertensivo el aliskiren ha demostrado un efecto protector a nivel renal y cardíaco (Pilz B. et al, 2005). También posee efectos positivos frente a la aterosclerosis (en modelos animales), reduce la proteinuria en pacientes diabéticos y ha demostrado efectos antiinflamatorios tanto a nivel renal como a nivel cardiovascular (Feldman DL. et al, 2008). Por su parte, la chemerina es una nueva adipocitoquina implicada en numerosos procesos inflamatorios, metabólicos y asociada con la obesidad y la diabetes mellitus de tipo II (Bozaoglu K. et al, 2007). La chemerina también podría participar en el desarrollo de enfermedades cardiovasculares ya que sus niveles en circulación se encuentran positivamente correlacionados con diferentes parámetros cardiometabólicos y con la severidad de la cardiopatía isquémica (Xiaotao L. et al, 2012). Por todo ello, nuestro objetivo es el de estudiar el papel del aliskiren y la chemerina en el metabolismo y la viabilidad de los cardiomiocitos y su posible implicación en la regulación de procesos inflamatorios a nivel cardíaco

Increased expression of fatty-acid and calcium metabolism genes in failing human heart

Background: 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. Methods: 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). Results: 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. Conclusion: 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

Nesfatin-1 in human and murine cardiomyocytes: synthesis, secretion, and mobilization of GLUT-4

Nesfatin-1, a satiety-inducing peptide identified in hypothalamic regions that regulate energy balance, is an integral regulator of energy homeostasis and a putative glucose-dependent insulin coadjuvant. We investigated its production by human cardiomyocytes and its effects on glucose uptake, in the main cardiac glucose transporter GLUT-4 and in intracellular signaling. Quantitative RT-PCR, Western blots, confocal immunofluorescence microscopy, and ELISA of human and murine cardiomyocytes and/or cardiac tissue showed that cardiomyocytes can synthesize and secrete nesfatin-1. Confocal microscopy of cultured cardiomyocytes after GLUT-4 labeling showed that nesfatin-1 mobilizes this glucose transporter to cell peripherals. The rate of 2-deoxy-D-[(3)H]glucose incorporation demonstrated that nesfatin-1 induces glucose uptake by HL-1 cells and cultured cardiomyocytes. Nesfatin-1 induced dose- and time-dependent increases in the phosphorylation of ERK1/2, AKT, and AS160. In murine and human cardiac tissue, nesfatin-1 levels varied with diet and coronary health. In conclusion, human and murine cardiomyocytes can synthesize and secrete nesfatin-1, which is able to induce glucose uptake and the mobilization of the glucose transporter GLUT-4 in these cells. Nesfatin-1 cardiac levels are regulated by diet and coronary health

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

Computational advances in polynomial optimization: RAPOSa, a freely available global solver

[Abstract]: In this paper we introduce RAPOSa, a global optimization solver specifically designed for (continuous) polynomial programming problems with box-constrained variables. Written entirely in C++, RAPOSa is based on the Reformulation-Linearization (Sherali and Tuncbilek in J Glob Optim 103:225–249, 1992). We present a description of the main characteristics of RAPOSa along with a thorough analysis of the impact on its performance of various enhancements discussed in the literature, such as bound tightening and SDP cuts. We also present a comparative study with three of the main state-of-the-art global optimization solvers: BARON, Couenne and SCIP.Ministerio de Ciencia y Tecnología; PID2021-124030NB-C32Ministerio de Educación; FPU Grant 17/02643Xunta de Galicia; ED431C-2020-14Xunta de Galicia; ED431G2019/0