JOSE EDUARDO KRIEGER

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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

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Autor: KRIEGER, Jose Eduardo × Colaboração internacional: Estados Unidos ×

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Agora exibindo 1 - 10 de 21
  • article 9 Citação(ões) na Scopus
    Characterization of post-edited cells modified in the TFAM gene by CRISPR/Cas9 technology in the bovine model
    (2020) OLIVEIRA, Vanessa Cristina de; MARIANO JUNIOR, Clesio Gomes; BELIZARIO, Jose Ernesto; KRIEGER, Jose Eduardo; BRESSAN, Fabiana Fernandes; ROBALLO, Kelly Cristine Santos; FANTINATO-NETO, Paulo; MEIRELLES, Flavio Vieira; CHIARATTI, Marcos Roberto; CONCORDET, Jean-Paul; AMBROSIO, Carlos Eduardo
    Gene editing in large animal models for future applications in translational medicine and food production must be deeply investigated for an increase of knowledge. The mitochondrial transcription factor A (TFAM) is a member of the HMGB subfamily that binds to mtDNA promoters. This gene maintains mtDNA, and it is essential for the initiation of mtDNA transcription. Lately, we generated a new cell line through the disruption of the TFAM gene in bovine fibroblast cells by CRISPR/Cas 9 technology. We showed that the CRISPR/Cas9 design was efficient through the generation of heterozygous mutant clones. In this context, once this gene regulates the mtDNA replication specificity, the study aimed to determine if the post-edited cells are capable of in vitro maintenance and assess if they present changes in mtDNA copies and mitochondrial membrane potential after successive passages in culture. The post-edited cells were expanded in culture, and we performed a growth curve, doubling time, cell viability, mitochondrial DNA copy number, and mitochondrial membrane potential assays. The editing process did not make cell culture unfeasible, even though cell growth rate and viability were decreased compared to control since we observed the cells grow well when cultured in a medium supplemented with uridine and pyruvate. They also exhibited a classical fibroblastoid appearance. The RT-qPCR to determine the mtDNA copy number showed a decrease in the edited clones compared to the non-edited ones (control) in different cell passages. Cell staining with Mitotracker Green and red suggests a reduction in red fluorescence in the edited cells compared to the non-edited cells. Thus, through characterization, we demonstrated that the TFAM gene is critical to mitochondrial maintenance due to its interference in the stability of the mitochondrial DNA copy number in different cell passages and membrane potential confirming the decrease in mitochondrial activity in cells edited in heterozygosis.
  • article 8 Citação(ões) na Scopus
    Endothelial, platelet, and macrophage microparticle levels do not change acutely following transcatheter aortic valve replacement
    (2016) MARCHINI, Julio F.; MIYAKAWA, Ayumi Aurea; TARASOUTCHI, Flavio; KRIEGER, Jose Eduardo; LEMOS, Pedro; CROCE, Kevin
    Background: Patients with severe aortic stenosis have increased levels of prothrombotic and proinflammatory microparticles (MP), and MPs actively regulate pathological processes that lead to atherothrombotic cardiovascular events. Shear stress is a validated stimulus of MP production, and abnormal shear stress in aortic stenosis increases MP release in ex-vivo studies. We hypothesized that in patients with severe aortic stenosis, percutaneous replacement of the aortic valve (TAVR) would reduce abnormal shear stress and would decrease levels of circulating MPs. Findings: The experimental protocol utilized flow cytometry (FC) and nanoparticle tracking analysis (NTA) to quantify circulating plasma MP levels in aortic stenosis patients at baseline and 5 days after TAVR. The baseline and 5 day MP counts measured by FC were 6.10.10(5) +/- 1.21.10(5) MP/mu L and 5.74.10(5) +/- 9.54.10(4) MP/mu L, respectively (p = 0.91). The baseline and 5 day MP counts measured by NTA were 9.29.10(13) +/- 1.66.10(13) MP/mu L and 3.95.10(14) +/- 3.11.10(14) MP/mu L, respectively (p = 0.91). When MPs were stratified by cell source, there was no difference in pre/post TAVR endothelial, platelet, or leukocyte MP levels. Conclusion: Levels of circulating MPs do not change acutely following TAVR therapy for aortic stenosis. Trial registered at clinicaltrials. gov NCT02193035 on July 11, 2014.
  • article 4 Citação(ões) na Scopus
    Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium
    (2022) ASSUNCAO-JR, Antonildes N.; ROCHITTE, Carlos Eduardo; KWONG, Raymond Y.; GOWDAK, Luis Henrique Wolff; KRIEGER, Jose Eduardo; JEROSCH-HEROLD, Michael
    OBJECTIVES This study investigated whether intramyocardial bone marrow-derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BACKGROUND Patients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. METHODS The MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. RESULTS Of 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 +/- 0.79 vs 1.64 +/- 0.89 in adjacent and 1.79 +/- 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). CONCLUSIONS BMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments. (J Am Coll Cardiol Img 2022;15:812-824) (c) 2022 The Authors.
  • article 6 Citação(ões) na Scopus
    Genomic ancestry as a predictor of haemodynamic profile in heart failure
    (2016) BERNARDEZ-PEREIRA, Sabrina; GIOLI-PEREIRA, Luciana; MARCONDES-BRAGA, Fabiana G.; SANTOS, Paulo Caleb Junior Lima; SPINA, Joceli Mabel Rocha; HORIMOTO, Andrea Roseli Vancan Russo; SANTOS, Hadassa Campos; BACAL, Fernando; FERNANDES, Fabio; MANSUR, Alfredo Jose; PIETROBON, Ricardo; KRIEGER, Jose Eduardo; MESQUITA, Evandro Tinoco; PEREIRA, Alexandre Costa
    Objective: The aim of this study is to assess the association between genetic ancestry, self-declared race and haemodynamic parameters in patients with chronic heart failure (HF). Methods: Observational, cross-sectional study. Eligible participants were aged between 18 and 80 years; ejection fraction was <= 50%. Patients underwent genetic analysis of ancestry informative markers, echocardiography and impedance cardiography (ICG). Race was determined by self-classification into two groups: white and non-white. Genomic ancestry was estimated using a panel of 101 348 polymorphic markers and three continental reference populations (European, African and Native American). Results: Our study included 362 patients with HF between August 2012 and August 2014. 123 patients with HF declared themselves as white and 234 patients declared themselves as non-white. No statistically significant differences were found regarding the ICG parameters according to self-declared race. The Amerindian ancestry was positively correlated with systolic time ratio (r=0.109, p<0.05). The thoracic fluid content index (r=0.124. p<0.05), E wave peak (r=0.127. p<0.05) and E/e' ratio (r=0.197. p<0.01) were correlated positively with African ancestry. In multiple linear regression, African ancestry remained associated with the E/e0 ratio, even after adjustment to risk factors. Conclusions: The African genetic ancestry was associated with worse parameters of diastolic function; the Amerindian ancestry correlated with a worse pattern of ventricular contractility, while self-declared colour was not helpful to infer haemodynamic profiles in HF.
  • article 1 Citação(ões) na Scopus
    Comparing different metabolic indexes to predict type 2 diabetes mellitus in a five years follow-up cohort: The Baependi Heart Study
    (2022) OLIVEIRA, Camila Maciel de; PAVANI, Jessica Leticia; LIU, Chunyu; BALCELLS, Mercedes; CAPASSO, Robson; ALVIM, Rafael de Oliveira; MOURAO-JUNIOR, Carlos Alberto; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    This study evaluates the association of anthropometric indexes and the incidence of type 2 diabetes mellitus (T2DM) after a 5-year follow-up. This analysis included 1091 middle-aged participants (57% women, mean age 47 +/- 15 years) who were free of T2DM at baseline and attended two health examinations cycles [cycle 1 (2005-2006) and cycle 2 (2010-2013)]. As expected, the participants who developed T2DM after five years (3.8%) had the worst metabolic profile with higher hypertension, dyslipidemia, and obesity rates. Besides, using mixed-effects logistic regression and adjustment for sex, age, and glucose, we found that one unit increase in body adiposity index (BAI) was associated with an 8% increase in their risk of developing T2DM (odds ratio [OR] = 1.08 [95% CI, 1.02-1.14]) and visceral adiposity index (VAI) was associated with a risk increase of 11% (OR = 1.11 [95% CI, 1.00-1.22]). Moreover, a one-unit increase in the triglycerides-glucose index (TyG) was associated with more than four times the risk of developing T2DM (OR = 4.27 [95% CI, 1.01-17.97]). The interquartile range odds ratio for the continuous predictors showed that TyG had the best discriminating performance. However, when any of them were additionally adjusted for waist circumference (WC) or even body mass index (BMI), all adiposity indexes lost the effect in predicting T2DM. In conclusion, TyG had the most substantial predictive power among all three indexes. However, neither BAI, VAI, nor TyG were superior to WC or BMI for predicting the risk of developing T2DM in a middle-aged normoglycemic sample in this rural Brazilian population.
  • article 22 Citação(ões) na Scopus
    Generation of induced pluripotent stem cells from large domestic animals
    (2020) BRESSAN, Fabiana Fernandes; BASSANEZZE, Vinicius; PESSOA, Lais Vicari de Figueiredo; SACRAMENTO, Chester Bittencourt; MALTA, Tathiane Maistro; KASHIMA, Simone; FANTINATO NETO, Paulo; STREFEZZI, Ricardo De Francisco; PIERI, Naira Caroline Godoy; KRIEGER, Jose Eduardo; COVAS, Dimas Tadeu; MEIRELLES, Flavio Vieira
    Background: Induced pluripotent stem cells (iPSCs) have enormous potential in developmental biology studies and in cellular therapies. Although extensively studied and characterized in human and murine models, iPSCs from animals other than mice lack reproducible results. Methods: Herein, we describe the generation of robust iPSCs from equine and bovine cells through lentiviral transduction of murine or human transcription factors Oct4, Sox2, Klf4, and c-Myc and from human and murine cells using similar protocols, even when different supplementations were used. The iPSCs were analyzed regarding morphology, gene and protein expression of pluripotency factors, alkaline phosphatase detection, and spontaneous and induced differentiation. Results: Although embryonic-derived stem cells are yet not well characterized in domestic animals, generation of iPS cells from these species is possible through similar protocols used for mouse or human cells, enabling the use of pluripotent cells from large animals for basic or applied purposes. Herein, we also infer that bovine iPS (biPSCs) exhibit similarity to mouse iPSCs (miPSCs), whereas equine iPSs (eiPSCs) to human (hiPSCs). Conclusions: The generation of reproducible protocols in different animal species will provide an informative tool for producing in vitro autologous pluripotent cells from domestic animals. These cells will create new opportunities in animal breeding through transgenic technology and will support a new era of translational medicine with large animal models.
  • article 12 Citação(ões) na Scopus
    Kinin-B2 Receptor Activity in Skeletal Muscle Regeneration and Myoblast Differentiation
    (2019) ALVES, Janaina M.; MARTINS, Antonio H.; LAMEU, Claudiana; GLASER, Talita; BOUKLI, Nawal M.; BASSANEZE, Vinicius; DARIOLLI, Rafael; NASCIMENTO, Isis C.; MARTINS, Poliana C. M.; SOUZA, Hellio D. N. de; KRIEGER, Jose Eduardo; CASARINI, Dulce E.; SALES, Vicencia M.; PESQUERO, Joao B.; ULRICH, Henning
    The bioactive peptide bradykinin obtained from cleavage of precursor kininogens activates the kinin-B2 receptor functioning in induction of inflammation and vasodilatation. In addition, bradykinin participates in kidney and cardiovascular development and neuronal and muscle differentiation. Here we show that kinin-B2 receptors are expressed throughout differentiation of murine C2C12 myoblasts into myotubes. An autocrine loop between receptor activation and bradykinin secretion is suggested, since bradykinin secretion is significantly reduced in the presence of the kinin-B2 receptor antagonist HOE-140 during differentiation. Expression of skeletal muscle markers and regenerative capacity were decreased after pharmacological inhibition or genetic ablation of the B2 receptor, while its antagonism increased the number of myoblasts in culture. In summary, the present work reveals to date no functions described for the B2 receptor in muscle regeneration due to the control of proliferation and differentiation of muscle precursor cells.
  • article 0 Citação(ões) na Scopus
    High-volume endurance exercise training stimulates hematopoiesis by increasing ACE NH2-terminal activity
    (2021) MAGALHAES, Flavio de Castro; FERNANDES, Tiago; BASSANEZE, Vinicius; MATTOS, Katt Coelho; SCHETTERT, Isolmar; MARQUES, Fabio Luiz Navarro; KRIEGER, Jose Eduardo; NAVA, Roberto; BARAUNA, Valerio Garrone; OLIVEIRA, Edilamar Menezes de
    One of the health benefits of endurance exercise training (ET) is the stimulation of hematopoiesis. However, the mechanisms underlying ET-induced hematopoietic adaptations are understudied. N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) inhibits proliferation of early hematopoietic progenitor cells. The angiotensin I-converting enzyme (ACE) NH2-terminal promotes hematopoiesis by inhibiting the anti-hematopoietic effect of Ac-SDKP. Here we demonstrate for the first time the role of ACE NH2-terminal in ET-induced hematopoietic adaptations. Wistar rats were subjected to 10 weeks of moderate-(T1) and high-(T2) volume swimming-training. Although both protocols induced classical ET-associated adaptations, only T2 increased plasma ACE NH2-domain activity (by 40%, P=0.0003) and reduced Ac-SDKP levels (by 50%, P<0.0001). T2 increased the number of hematopoietic stem cells (HSCs; similar to 200%, P=0.0008), early erythroid progenitor colonies (similar to 300%, P<0.0001) and reticulocytes (similar to 500%, P=0.0007), and reduced erythrocyte lifespan (similar to 50%, P=0.022). Following, Wistar rats were subjected to T2 or T2 combined with ACE NH2-terminal inhibition (captopril (Cap) treatment: 10 mg.kg(-1).day(-1)). T2 combined with ACE NH2-terminal inhibition prevented Ac-SDKP decrease and attenuated ET-induced hematopoietic adaptations. Altogether, our findings show that ET-induced hematopoiesis was at least partially associated with increased ACE NH2-terminal activity and reduction in the hematopoietic inhibitor Ac-SDKP.
  • article 0 Citação(ões) na Scopus
    Integrated systems biology approach identifies gene targets for endothelial dysfunction
    (2023) PINHEIRO-DE-SOUSA, Iguaracy; FONSECA-ALANIZ, Miriam Helena; GIUDICE, Girolamo; VALADAO, Iuri Cordeiro; MODESTIA, Silvestre Massimo; MATTIOLI, Sarah Viana; ROSA JUNIOR, Ricardo; ZALMAS, Lykourgos-Panagiotis; FANG, Yun; PETSALAKI, Evangelia; KRIEGER, Jose Eduardo
    Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening, high content imaging and network analysis to prioritise key ED genes and identify a pro- and anti-ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro-ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti-ED network was enriched in hypoxia, angiogenesis and cancer-related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease-specific candidate drug targets for endothelial dysfunction. imageMulti-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.Multi-omics data integration of endothelial cells treated with mimics of major cardiovascular disease factors identified 81 putative endothelial dysfunction (ED) genes.Upon siRNA-mediated gene knockdown, 83% of ED gene candidates affected at least one ED phenotype (26 exacerbating and 31 ameliorating the ED phenotypes).The analyses reveal emergent properties of disease networks, distinguishing between adaptation and rewiring for survival and those associated with deregulation that can be targeted for ED treatment.An orthogonal drug screen on treated endothelial cells provided additional support for DUSP1, IL6 and CCL2 as putative targets for ED. Multi-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.image
  • article 22 Citação(ões) na Scopus
    Poor sleep quality and lipid profile in a rural cohort (The Baependi Heart Study)
    (2019) GEOVANINI, Glaucylara Reis; LORENZI-FILHO, Geraldo; PAULA, Lilian K. de; OLIVEIRA, Camila Maciel; ALVIM, Rafael de Oliveira; BEIJAMINI, Felipe; NEGRAO, Andre Brooking; SCHANTZ, Malcolm von; KNUTSON, Kristen L.; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa
    Aim: To test the association between cardiometabolic risk factors and subjective sleep quality assessed by the Pittsburgh sleep quality index (PSQI), independent of obstructive sleep apnea (OSA) and sleep duration. Methods: A total of 573 participants from the Baependi Heart Study, a rural cohort from Brazil, completed sleep questionnaires and underwent polygraphy for OSA evaluation. Multivariable linear regression analysis tested the association between cardiovascular risk factors (outcome variables) and sleep quality measured by PSQI, adjusting for OSA and other potential confounders (age, sex, race, salary/wage, education, marital status, alcohol intake, obesity, smoking, hypertension, and sleep duration). Results: The sample mean age was 43 +/- 16 years, 66% were female, and mean body mass index (BMI) was 26 +/- 5 kg/m(2). Only 20% were classified as obese (BMI >= 30). Overall, 50% of participants reported poor sleep quality as defined by a PSQI score >= 5. A high PSQI score was significantly associated with higher very-low-density lipoprotein (VLDL) cholesterol levels (beta = 0.392, p = 0.012) and higher triglyceride levels (beta = 0.017, p = 0.006), even after adjustments, including the apneaehypopnea index. Further adjustments accounting for marital status, alcohol intake, and medication use did not change these findings. No significant association was observed between PSQI scores and glucose or blood pressure. According to PSQI components, sleep disturbances (beta = 1.976, p = 0.027), sleep medication use (beta = 1.121, p = 0.019), and daytime dysfunction (beta = 1.290, p = 0.024) were significantly associated with higher VLDL serum levels. Only the daytime dysfunction domain of the PSQI components was significantly associated with higher triglyceride levels (beta = 0.066, p = 0.004). Conclusion: Poorer lipid profile was independently associated with poor sleep quality, assessed by the PSQI questionnaire, regardless of a normal sleep duration and accounting for OSA and socio-economic status.