VICTOR DEBBAS

(Fonte: Lattes)
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Departamento de Cardio-Pneumologia, Faculdade de Medicina
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina

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  • article 17 Citação(ões) na Scopus
    Cellular prion protein (PrPC) and superoxide dismutase (SOD) in vascular cells under oxidative stress
    (2011) SOPRANA, Helen Zocche; SOUZA, Liliete Canes; DEBBAS, Victor; LAURINDO, Francisco Rafael Martins
    The PrPC is expressed in several cell types but its physiological function is unknown. Some studies associate the PrPC with copper metabolism and the antioxidant activity of SOD. Our hypothesis was that changes in PrPC expression lead to abnormal copper regulation and induce SOD downregulation in the vascular wall. Objectives: to study whether the PrPC expression undergoes induction by agents that trigger endoplasmic reticulum stress (ERS) and, in this context, to evaluate the SOD activity. Methods: To trigger ERS, in vitro, rabbit aortic smooth muscle cells were challenged for 4, 8 and 18 hours, with angiotensin-II, tunicamycin and 7-ketocholesterol. For in vivo studies rabbit aortic arteries were subjected to injury by balloon catheter. Results: In vitro baseline SOD activity, determined through inhibition of cytochrome-c reduction, was 13.9 +/- 1.2 U/mg protein, angiotensin-II exposed for 8 hours produced an increase in SOD activity, and cellular copper concentration was about 9 times greater only under these conditions. Western blotting analysis for SOD isoenzymes showed an expression profile that was not correlated with the enzymatic activity. PrPC expression decreased after exposure to all agents after different incubation periods. RT-PCR assay showed increased mRNA expression for PrPC only in cells stimulated for 8 hours with the different stressors. The PrPC mRNA expression in rabbit aortic artery fragments, subjected to balloon catheter injury, showed a pronounced increase immediately after overdistension. The results obtained indicated a PrPC protection factor during the early part of the ERS exposure period, but did not demonstrate a SOD-like profile for the PrPC.
  • article 20 Citação(ões) na Scopus
    Protein disulfide isomerase plasma levels in healthy humans reveal proteomic signatures involved in contrasting endothelial phenotypes
    (2019) OLIVEIRA, Percillia Victoria Santos de; GARCIA-ROSA, Sheila; SACHETTO, Ana Teresa Azevedo; MORETTI, Ana Iochabel Soares; DEBBAS, Victor; BESSA, Tiphany Coralie De; SILVA, Nathalia Tenguan; PEREIRA, Alexandre da Costa; MARTINS-DE-SOUZA, Daniel; SANTORO, Marcelo Larami; LAURINDO, Francisco Rafael Martins
    Redox-related plasma proteins are candidate reporters of protein signatures associated with endothelial structure/function. Thiol-proteins from protein disulfide isomerase (PDI) family are unexplored in this context. Here, we investigate the occurrence and physiological significance of a circulating pool of PDI in healthy humans. We validated an assay for detecting PDI in plasma of healthy individuals. Our results indicate high inter-individual (median = 330 pg/mL) but low intra-individual variability over time and repeated measurements. Remarkably, plasma PDI levels could discriminate between distinct plasma proteome signatures, with PDI-rich ( > median) plasma differentially expressing proteins related to cell differentiation, protein processing, housekeeping functions and others, while PDI-poor plasma differentially displayed proteins associated with coagulation, inflammatory responses and immunoactivation. Platelet function was similar among individuals with PDI-rich vs. PDI-poor plasma. Remarkably, such protein signatures closely correlated with endothelial function and phenotype, since cultured endothelial cells incubated with PDI-poor or PDI-rich plasma recapitulated gene expression and secretome patterns in line with their corresponding plasma signatures. Furthermore, such signatures translated into functional responses, with PDI-poor plasma promoting impairment of endothelial adhesion to fibronectin and a disturbed pattern of wound-associated migration and recovery area. Patients with cardiovascular events had lower PDI levels vs. healthy individuals. This is the first study describing PDI levels as reporters of specific plasma proteome signatures directly promoting contrasting endothelial phenotypes and functional responses.
  • article 10 Citação(ões) na Scopus
    SMALL INTERFERING RNA TARGETING FOCAL ADHESION KINASE PREVENTS CARDIAC DYSFUNCTION IN ENDOTOXEMIA
    (2012) GUIDO, Maria C.; CLEMENTE, Carolina F.; MORETTI, Ana I.; BARBEIRO, Hermes V.; DEBBAS, Victor; CALDINI, Elia G.; FRANCHINI, Kleber G.; SORIANO, Francisco G.
    Sepsis and septic shock are associated with cardiac depression. Cardiovascular instability is a major cause of death in patients with sepsis. Focal adhesion kinase (FAK) is a potential mediator of cardiomyocyte responses to oxidative and mechanical stress. Myocardial collagen deposition can affect cardiac compliance and contractility. The aim of the present study was to determine whether the silencing of FAK is protective against endotoxemia-induced alterations of cardiac structure and function. In male Wistar rats, endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (10 mg/kg). Cardiac morphometry and function were studied in vivo by left ventricular catheterization and histology. Intravenous injection of small interfering RNA targeting FAK was used to silence myocardial expression of the kinase. The hearts of lipopolysaccharide-injected rats showed collagen deposition, increased matrix metalloproteinase 2 activity, and myocyte hypertrophy, as well as reduced 24-h +dP/dt and -dP/dt, together with hypotension, increased left ventricular end-diastolic pressure, and elevated levels of FAK (phosphorylated and unphosphorylated). Focal adhesion kinase silencing reduced the expression and activation of the kinase in cardiac tissue, as well as protecting against the increased collagen deposition, greater matrix metalloproteinase 2 activity, and reduced cardiac contractility that occur during endotoxemia. In conclusion, FAK is activated in endotoxemia, playing a role in cardiac remodeling and in the impairment of cardiac function. This kinase represents a potential therapeutic target for the protection of cardiac function in patients with sepsis.
  • conferenceObject
    Protein Disulfide Isomerase-A1 Overexpression Attenuates Vascular Calcification in Vivo
    (2020) PESCATORE, Luciana; NOLASCO, Patricia; FESSEL, Melissa; ALMEIDA, Youri; WOSNIAK JR., Joao; DEBBAS, Victor; GAMARRA, Lionel; LIBERMAN, Marcel; LAURINDO, Francisco R.
  • article 8 Citação(ões) na Scopus
    Fibrillin-1 mg Delta(lPn) Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint
    (2016) MEIRELLES, Thayna; ARAUJO, Thais L. S.; NOLASCO, Patricia; MORETTI, Ana I. S.; GUIDO, Maria C.; DEBBAS, Victor; PEREIRA, Lygia V.; LAURINDO, Francisco R.
    Fibrillin-1 mutations promote Marfan syndrome (MFS) via complex yet unclear pathways. The roles of endoplasmic reticulum (ER) and the major ER redox chaperone protein disulfide isomerase-A1 in the processing of normal and mutated fibrillin-1 and ensuing protein secretion and/or intracellular retention are unclear. Our results in mouse embryonic fibroblasts bearing the exon-skipping mg Delta(lox-p-neo) (mg Delta(lpn)) mutation, which associates in vivo with MFS and in vitro with disrupted microfibrils, indicate a preserved ER-dependent proteostasis or redox homeostasis. Rather, mutated fibrillin-1 is secreted normally through Golgi-dependent pathways and is not intracellularly retained. Similar results occurred for the C1039G point mutation. In parallel, we provide evidence that PDIA1 physically interacts with fibrillin-1 in the ER. Moreover, siRNA against PDIA1 augmented fibrillin-1 secretion rates in wild-type cells. However, fibrillin-1 with the mg Delta(lpn) mutation bypassed PDI checkpoint delay, while the C1039G mutation did not. This heretofore undisclosed PDIA1-mediated mechanism may be important to control the extracellular availability of function-competent fibrillin-1, an important determinant of disease phenotype. Moreover, our results may reveal a novel, holdase-like, PDI function associated with ER protein quality control.
  • article 9 Citação(ões) na Scopus
    Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model
    (2018) GUIDO, Maria C.; DEBBAS, Victor; SALEMI, Vera M.; TAVARES, Elaine R.; MEIRELLES, Thayna; ARAUJO, Thais L. S.; NOLASCO, Patricia; FERREIRA-FILHO, Julio C. A.; TAKIMURA, Celso K.; PEREIRA, Lygia V.; LAURINDO, Francisco R.
    Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mg Delta(loxPneo) mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.
  • conferenceObject
    Talin and Src protein phosphorylation in hyperractive platelets
    (2013) FRIES, D. M.; DEBBAS, V; NEIVA, T. J. C.; OLIVEIRA, V De; SANTORO, M. L.; LEME, A. F. Paes; ROCHA, T. R. F.; D'AMICO, E. A.
  • article 24 Citação(ões) na Scopus
    Long-term exposure to high-sucrose diet down-regulates hepatic endoplasmic reticulum-stress adaptive pathways and potentiates de novo lipogenesis in weaned male mice
    (2018) FLISTER, Karla Frida Torres; PINTO, Bruno Araujo Serra; FRANCA, Lucas Martins; COELHO, Caio Fernando Ferreira; SANTOS, Pamela Costa dos; VALE, Caroline Castro; KAJIHARA, Daniela; DEBBAS, Victor; LAURINDO, Francisco Rafael Martins; PAES, Antonio Marcus de Andrade
    Childhood consumption of added sugars, such as sucrose, has been associated to increased risk of metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Although the mechanisms underlying NAFLD onset are incompletely defined, recent evidence has proposed a role for the endoplasmic reticulum (ER) stress. Thus, the present study sought to investigate the metabolic outcomes of high-sucrose intake on weaned Swiss mice fed a 25% sucrose diet for 30, 60 and 90 days in comparison to regular chow-fed controls. High-sucrose feeding promoted progressive metabolic and oxidative disturbances, starting from fasting and fed hyperglycemia, hyperinsulinemia, glucose intolerance and increased adiposity at 30-days; passing by insulin resistance, hypertriglyceridemia and NAFLD onset at 60 days; until late hepatic oxidative damage at 90 days. In parallel, assessment of transcriptional and/or translational levels of de novo lipogenesis (DNL) and ER stress markers showed up-regulation of both fatty acid synthesis (ChREBP and SCD1) and oxidation (PPAR alpha and CPT-1 alpha), as well as overexpression of unfolded protein response sensors (IRE1 alpha, PERK and ATF6), chaperones (GRP78 and PDIA1) and antioxidant defense (NRF2) genes at 30 days. At 60 days, fatty acid oxidation genes were down-regulated, and ER stress switched over toward a proapoptotic pattern via up-regulation of BAK protein and CHOP gene levels. Finally, down-regulation of both NRF2 and CPT-1 alpha protein levels led to late up-regulation of SREBP-1c and exponential raise of fatty acids synthesis. In conclusion, our study originally demonstrates a temporal relationship between DNL and ER stress pathways toward MetS and NAFLD development on weaned rats fed a high-sucrose diet.
  • conferenceObject
    Protein Disulfide Isomerase-A1 (PDIA1) Remodels Endoplasmic Reticulum -Plasma Membrane Contact Sites: Possible Role of Nogo-B Protein Regulation
    (2022) BESSA, Tiphany De; OLIVEIRA, Percillia; DEBBAS, Victor; WOSNIAK JR., Joao; SANTOS, Celio; SHAH, Ajay; LAURINDO, Francisco R.
  • article 15 Citação(ões) na Scopus
    Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer
    (2019) SALES, Allan Robson Kluser; NEGRAO, Marcelo Vailati; TESTA, Laura; FERREIRA-SANTOS, Larissa; GROEHS, Raphaela Villar Ramalho; CARVALHO, Bruna; TOSCHI-DIAS, Edgar; ROCHA, Natalia Galito; LAURINDO, Francisco Rafael Martins; DEBBAS, Victor; RONDON, Maria Urbana P. B.; MANO, Max Sena; HAJJAR, Ludhmila Abrahao; HOFF, Paulo Marcelo Gehm; KALIL FILHO, Roberto; NEGRAO, Carlos Eduardo
    The purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 +/- 2.0 yr; body mass index: 24.2 +/- 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m (2)) and CY (600 mg/m(2)) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP: finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs: flow cytometry). a surrogate marker for endothelial damage. MSNA and BP responses were increased (P < 0.001), whereas CBF and CVC responses were decreased (P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT (P = 0.03, CHT vs. SL session). No difference in HR response was observed (P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.