JOSE EDUARDO KRIEGER
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
6 resultados
Resultados de Busca
Agora exibindo 1 - 6 de 6
- High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells(2021) GIRAO-SILVA, T.; FONSECA-ALANIZ, M. H.; RIBEIRO-SILVA, J. C.; LEE, J.; PATIL, N. P.; DALLAN, L. A.; BAKER, A. B.; HARMSEN, M. C.; KRIEGER, J. E.; MIYAKAWA, A. A.The rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin's nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.
- Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits(2021) SUN, D.; RICHARD, M. A.; MUSANI, S. K.; SUNG, Y. J.; WINKLER, T. W.; SCHWANDER, K.; CHAI, J. F.; GUO, X.; KILPELäINEN, T. O.; VOJINOVIC, D.; ASCHARD, H.; HORTA, B. L.; LIU, C.-T.; BIELAK, L. F.; MOOK-KANAMORI, D. O.; MORRISON, A. C.; PEREIRA, A. C.; PSATY, B. M.; AMIN, N.; FOX, E. R.; KOOPERBERG, C.; WEN, W.; SIM, X.; BIERUT, L.; ROTTER, J. I.; BROWN, M. R.; KARDIA, S. L. R.; FRANCESCHINI, N.; RAO, D. C.; FORNAGE, M.; Lifelines Cohort Study; CHITRALA, K.; YANEK, L. R.; HARTWIG, F. P.; HORIMOTO, A. R. V. R.; LIU, Y.; MANNING, A. K.; NOORDAM, R.; SMITH, A. V.; HARRIS, S. E.; KüHNEL, B.; LYYTIKäINEN, L.-P.; NOLTE, I. M.; ARKING, D. E.; RAURAMAA, R.; MOST, P. J. van der; WANG, R.; WARE, E. B.; WEISS, S.; ARNETT, D. K.; BARAC, A.; BOERWINKLE, E.; BROECKEL, U.; CHAKRAVARTI, A.; CHEN, Y.-D. I.; CUPPLES, L. A.; LUIK, A. I.; DAVIGULUS, M. L.; FUENTES, L. de las; MUTSERT, R. de; VRIES, P. S. de; DELANEY, J. A. C.; ROUX, A. V. Diez; DöRR, M.; FAUL, J. D.; FRETTS, A. M.; GALLO, L. C.; MARTIN, L. W.; GRABE, H. J.; GU, C. C.; HARRIS, T. B.; HARTMAN, C. C. A.; HEIKKINEN, S.; IKRAM, M. A.; ISASI, C.; JOHNSON, W. C.; JONAS, J. B.; KAPLAN, R. C.; MEITINGER, T.; KOMULAINEN, P.; KRIEGER, J. E.; LEVY, D.; LIU, J.; LOHMAN, K.; MILANESCHI, Y.; O'CONNELL, J. R.; PALMAS, W. R.; PETERS, A.; PEYSER, P. A.; PULKKI-RåBACK, L.; RAFFEL, L. J.; ZHAO, W.; REINER, A. P.; RICE, K.; ROBINSON, J. G.; ROSENDAAL, F. R.; SCHMIDT, C. O.; SCHREINER, P. J.; SCHWETTMANN, L.; SHIKANY, J. M.; SHU, X.-O.; SIDNEY, S.; ZHU, X.; SIMS, M.; SMITH, J. A.; SOTOODEHNIA, N.; STRAUCH, K.; TAI, E. S.; TAYLOR, K. D.; UITTERLINDEN, A. G.; DUIJN, C. M. van; WALDENBERGER, M.; WEE, H.-L.; ZONDERMAN, A. B.; WEI, W.-B.; WILSON, G.; XUAN, D.; YAO, J.; ZENG, D.; BECKER, D. M.; DEARY, I. J.; GIEGER, C.; LAKKA, T. A.; LEHTIMäKI, T.; NORTH, K. E.; OLDEHINKEL, A. J.; BARTZ, T. M.; PENNINX, B. W. J. H.; SNIEDER, H.; WANG, Y.-X.; WEIR, D. R.; ZHENG, W.; EVANS, M. K.; GAUDERMAN, W. J.; GUDNASON, V.Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value < 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations. © 2020 The Author(s)
- Dynamic Crosstalk between Vascular Smooth Muscle Cells and the Aged Extracellular Matrix(2021) RIBEIRO-SILVA, Joao Carlos; NOLASCO, Patricia; KRIEGER, Jose Eduardo; MIYAKAWA, Ayumi AureaVascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases.
- Metabolomic Evaluation of Chronic Periodontal Disease in Older Adults(2021) RODRIGUES, Wellington F.; MIGUEL, Camila B.; AGOSTINHO, Ferdinando; V, Gabriela da Silva; LAZO-CHICA, Javier E.; SCAPIN, Sandra M. Naressi; NAPIMOGA, Marcelo H.; TRINDADE-DA-SILVA, Carlos A.; KRIEGER, Jose E.; PEREIRA, Alexandre da Costa; OLIVEIRA, Carlo J. Freire; SOARES, Siomar de Castro; UEIRA-VIEIRA, Carlos; KLEINJAN, AlexPeriodontal disease is an infectious inflammatory disease related to the destruction of supporting tissues of the teeth, leading to a functional loss of the teeth. Inflammatory molecules present in the exudate are catalyzed and form different metabolites that can be identified and quantified. Thus, we evaluated the inflammatory exudate present in crevicular fluid to identify metabolic biological markers for diagnosing chronic periodontal disease in older adults. Research participants were selected from long-term institutions in Brazil. Participants were individuals aged 65 years or older, healthy, or with chronic periodontal disease. Gas chromatography/mass spectrometry was used to evaluate potential biomarkers in 120 crevicular fluid samples. We identified 969 metabolites in the individuals. Of these, 15 metabolites showed a variable importance with projection score>1 and were associated with periodontal disease. Further analysis showed that among the 15 metabolites, two (5-aminovaleric acid and serine, 3TMS derivative) were found at higher concentrations in the crevicular fluid, indicating their potential diagnostic power for periodontal disease in older adults. Our findings indicated that some metabolites are present at high concentrations in the crevicular fluid in older adults with periodontal disease and can be used as biomarkers of periodontal disease.
- Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study(2021) BENSENOR, Isabela; PADILHA, Kallyandra; LIMA, Isabella Ramos; SANTOS, Raul Dias; LAMBERT, Gilles; RAMIN-MANGATA, Stephane; BITTENCOURT, Marcio S.; GOULART, Alessandra C.; SANTOS, Itamar S.; MILL, Jose G.; KRIEGER, Jose E.; LOTUFO, Paulo A.; PEREIRA, Alexandre C.Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1x10(-6). Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.
- Sex differences in the lung ACE/ACE2 balance in hypertensive rats(2021) MARTINS, Flavia L.; TAVARES, Caio A. M.; MALAGRINO, Pamella A.; RENTZ, Thiago; BENETTI, Acaris; RIOS, Thiago M. S.; PEREIRA, Gabriel M. D.; CARAMELLI, Bruno; TEIXEIRA, Samantha K.; KRIEGER, Jose E.; GIRARDI, Adriana C. C.The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 +/- 17 vs. 43 +/- 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).