Browsing by Author "Krause, Bernardo J."
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- ItemChronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition(2018) Krause, Bernardo J.; Casanello Toledo, Paola Cecilia; Dias, Ana C.; Arias, Paulina; Velarde, Victoria; Arenas Menéndez, German Alberto; Preite, Marcelo Daniel; Iturriaga Agüera, Rodrigo
- ItemINTRAUTERINE GROWTH RESTRICTION IN GUINEA PIG IMPAIRS UMBILICAL AND SYSTEMIC VASCULAR FUNCTION(W B SAUNDERS CO LTD, 2015) Herrera, Emilio A.; Schneider, Daniela; Alegria, Rene; Figueroa, Esteban; Villanueva, Cristian; Farias, Marcelo; Casanello, Paola; Krause, Bernardo J.
- ItemMaternal obesity and high leptin levels prime pro-inflammatory pathways in human cord blood leukocytes(2023) Krause, Bernardo J.; Vega-Tapia, Fabian A.; Soto-Carrasco, Gustavo; Lefever, Isidora; Letelier, Catalina; Saez, Claudia G.; Castro-Rodriguez, Jose A.Introduction: Maternal obesity alters the immune function in the offspring. We hypothesize that maternal obesity and pro-inflammatory pathways induce leptin-related genes in neonatal monocytes, whereby high leptin levels enhance their inflammatory response. Methods: Transcriptional profiles of cord blood leukocytes (CBL) in basal and pro-inflammatory conditions were studied to determine differentially expressed genes (DEG). The DNA methylation profile of CB monocytes (CBM) of neonates born to control BMI mothers and women with obesity was assayed to identify differentially methylated probes (DMP). CBM-derived macrophages were cultured with or without leptin (10-100 ng/ml) and then stimulated with lipopolysaccharide (LPS, 100 ng/ml) and interferon-gamma (20 ng/ml) to assess the induction of TNF-& alpha; and IL-10 transcripts. Results: CBL from pregnancies with obesity (CBL-Ob) showed 12,183 DEG, affecting 49 out of 78 from the leptin pathway. Control CBM exposed to LPS showed 45 leptin-related DEG, an effect prevented by the co-exposure to LPS and IL-10. Conversely, CBM-Ob showed 5279 DMP enriched in insulin- and leptin-related genes, and Lasso regression of leptin-related DMP showed high predictive value for plasma leptin levels (r2 = 0.9897) and maternal BMI categories (AUC = 1). Chronic exposure to leptin increased TNF-& alpha; and decreased IL-10 levels in control BMI samples but not in Ob-CBM. Enhanced TNF-& alpha; induction after proinflammatory stimulation was observed in leptin-treated control BMI samples. Discussion: Obesity in pregnancy is associated with a distinctive expression and DNA methylation profile of leptin-related genes in cord blood monocytes, meanwhile, leptin enhances the expression of pro-inflammatory cytokines upon stimulation with M1-skewing agents.
- ItemMaternal obesity is associated with a sex-specific epigenetic programming in human neonatal monocytes(2020) Vega-Tapia, Fabian; Artigas, Rocio; Hernandez, Cherie; Uauy, Ricardo; Casanello, Paola; Krause, Bernardo J.; Castro-Rodriguez, Jose A.Aim: To determine changes in global DNA methylation in monocytes from neonates of women with obesity, as markers of an immune programming resulting from maternal obesity. Materials & methods: Cord blood monocytes were obtained from neonates born to women with obesity and normal weight, genome-wide differentially methylated CpGs were determined using an Infinium MethylationEPIC-BeadChip (850K). Results: No clustering of samples according to maternal BMI was observed, but sex-specific analysis revealed 71,728 differentially methylated CpGs in female neonates from women with obesity (p < 0.01). DAVID analysis showed increased methylation levels within genes involved in the innate immune response and inflammation. Conclusion: Maternal obesity induces, in a sex-specific manner, an epigenetic programming of monocytes that could contribute to disease later in life.
- ItemNonsyndromic orofacial clefts in Chile: LINE-1 methylation and MTHFR variants(2020) Cáceres Rojas, Gabriela; Salamanca, Carlos; Krause, Bernardo J.; Recabarren, Andrea S.; Pantoja, Roberto; Leiva, Noemi; Pardo, Rosa; Santos Martín, José Luis; Suazo, JoséAim: To evaluate the risk of nonsyndromic orofacial clefts (NSOFCs) associated with LINE-1 methylation, as a marker of global DNA methylation, and the effect of MTHFR functional variants on this variable. Patients & methods: LINE-1 methylation was evaluated by bisulfite modification coupled to DNA pyrosequencing in 95 NSOFC cases and 95 controls. In these subjects, MTHFR genotypes for variants c.C677T (rs1801133) and c.A1298C (rs1801131) were obtained. Results: Middle levels (second tertile) of LINE-1 methylation increase the risk of NSOFCs. In addition, LINE-1 methylation depends on c.A1298C genotypes in controls but not in cases. Conclusion: A nonlinear association between global DNA methylation and NSOFCs was detected in this Chilean population, which appears to be influenced by MTHFR functional variants.
- ItemSildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep(INT PEDIATRIC RESEARCH FOUNDATION, INC, 2008) Herrera, Emilio A.; Ebensperger, German; Krause, Bernardo J.; Riquelme, Raquel A.; Reyes, Roberto V.; Capetillo, Maria; Gonzalez, Sergio; Parer, Julian T.; Llanos, Anibal J.Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small Pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.
- ItemThe asthma predictive index as a surrogate diagnostic tool in preschoolers: Analysis of a longitudinal birth cohort(WILEY, 2021) Castro Rodriguez, Jose A.; Forno, Erick; Padilla, Oslando; Casanello, Paola; Krause, Bernardo J.; Borzutzky Schachter, ArturoDiagnosing asthma in preschool children remains an unsolved challenge, at a time when early identification would allow for better education and treatment to prevent morbidity and lung function deterioration. Objective To evaluate if the asthma predictive index (API) can be used as surrogate for asthma diagnosis in preschoolers. Methods Birth cohort of 339 pregnant women enrolled at delivery and their offspring, who were followed for atopy, wheezing, and other respiratory illnesses through 30 months of age. The API was determined at 30 months of age by the researchers; and examined its association with physician-diagnosed asthma during the first 30 months, made independently by the primary care physician not involved in the study. Results Among 307 offspring with complete follow-up, 44 (14.3%) were API+. Maternal body mass index, maternal education, past oral contraceptive use, birthweight, placenta weight, age of daycare at 12 m, gastroesophageal reflux disease at 12 m, acute otitis media at 18 m, bronchiolitis, croup and pneumonia, cord blood adiponectin were all associated with API+. In the multivariable analysis, API+ was associated with almost sixfold odds of asthma diagnosis (adjusted OR = 5.7, 95% CI [2.6-12.3]), after adjusting for the relevant covariates above including respiratory infections like bronchiolitis and pneumonia. The API sensitivity was 48%, specificity 92%, 61% PPV, 88% NPV, 6.4 LR+, 0.56 LR-, 0.84 diagnosis accuracy. The adjusted odds for asthma was 11.4. Conclusions This longitudinal birth cohort suggests, for first time, that API (a structured definition for asthma), could be used as a diagnostic tool, not only as a prognostic tool, in toddlers and preschoolers.
- ItemTranscriptional and Epigenomic Markers of the Arterial-Venous and Micro/Macro-Vascular Endothelial Heterogeneity within the Umbilical-Placental Bed(2022) Arenas, German A.; Santander, Nicolas; Krause, Bernardo J.Umbilical and placental vessels and endothelial cells (EC) are common models to study placental function and vascular programming. Arterio-venous differences are present in the umbilical endothelium; however, the heterogeneity of small placental vessels and the expression of potential micro- vs. macro-vascular (MMV) markers are poorly described. Here, we performed a meta-analysis of transcriptomic and DNA methylation data from placental and umbilical EC. Expression and methylation profiles were compared using hierarchical clustering, dimensionality reduction (i.e., tSNE, MDS, and PHATE), and enrichment analysis to determine the occurrence of arterio-venous (AVH) and micro-macro heterogeneity (MMH). CpG sites correlated with gene expression of transcriptional markers of MMH and AVH were selected by Lasso regression and used for EC discrimination. General transcriptional profile resulted in clear segregation of EC by their specific origin. MM and AVH grouping were also observed when microvascular markers were applied. Altogether, this meta-analysis provides cogent evidence regarding the transcriptional and epigenomic profiles that differentiate among EC, proposing novel markers to define phenotypes based on MM levels.
- ItemTranscriptional Profiling of Human Endothelial Cells Unveils PIEZO1 and Mechanosensitive Gene Regulation by Prooxidant and Inflammatory Inputs(2023) Arenas, German A.; Valenzuela, Jose G.; Penaloza, Estefania; Paz, Adolfo A.; Iturriaga, Rodrigo; Saez, Claudia G.; Krause, Bernardo J.PIEZO1 is a mechanosensitive cation channel implicated in shear stress-mediated endothelial-dependent vasorelaxation. Since altered shear stress patterns induce a pro-inflammatory endothelial environment, we analyzed transcriptional profiles of human endothelial cells to determine the effect of altered shear stress patterns and subsequent prooxidant and inflammatory conditions on PIEZO1 and mechanosensitive-related genes (MRG). In silico analyses were validated in vitro by assessing PIEZO1 transcript levels in both the umbilical artery (HUAEC) and vein (HUVEC) endothelium. Transcriptional profiling showed that PIEZO1 and some MRG associated with the inflammatory response were upregulated in response to high (15 dyn/cm(2)) and extremely high shear stress (30 dyn/cm(2)) in HUVEC. Changes in PIEZO1 and inflammatory MRG were paralleled by p65 but not KLF or YAP1 transcription factors. Similarly, PIEZO1 transcript levels were upregulated by TNF-alpha (TNF-alpha) in diverse endothelial cell types, and pre-treatment with agents that prevent p65 translocation to the nucleus abolished PIEZO1 induction. ChIP-seq analysis revealed that p65 bonded to the PIEZO1 promoter region, an effect increased by the stimulation with TNF-alpha. Altogether this data showed that NF-kappa B activation via p65 signaling regulates PIEZO1 expression, providing a new molecular link for prooxidant and inflammatory responses and mechanosensitive pathways in the endothelium.