VICTOR DEBBAS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina
11 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 11
- 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 MartinsRedox-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.
- 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.
- 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.
- 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 AndradeChildhood 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.
- 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.
conferenceObject Chemotheraphy acutely impairs neurovascular and hemodynamic responses in patients with breast cancer(2019) SALES, Allan Kluser; NEGRAO, Marcelo; TESTA, Laura; FERREIRA-SANTOS, Larissa; GROEHS, Raphaela; CARVALHO, Bruna; TOSCHI-DIAS, Edgar; ROCHA, Natalia; LAURINDO, Francisco; DEBBAS, Victor Kluser; RONDON, Maria Kluser; MANO, Max; HAJJAR, Ludhmila; HOFF, Paulo; FILHO, Robero; NEGRAO, Carlos- CD100 and plexins B2 and B1 mediate monocyte-endothelial cell adhesion and might take part in atherogenesis(2015) LUQUE, Maria Carolina A.; GUTIERREZ, Paulo S.; DEBBAS, Victor; KALIL, Jorge; STOLF, Beatriz S.Leukocyte migration is essential for the function of the immune system. Their recruitment from the vessels to the tissues involves sequential molecular interactions between leukocytes and endothelial cells (ECs). Many adhesion molecules involved in this process have already been described. However, additional molecules may be important in this interaction, and here we explore the potential role for CD100 and plexins in monocyte-EC binding. CD100 was shown to be involved in platelet-endothelial cell interaction, an important step in atherogenesis and thrombus formation. In a recent work we have described CD100 expression in monocytes and in macrophages and foam cells of human atherosclerotic plaques. In the present work, we have identified plexin B2 as a putative CD100 receptor in these cells. We have detected CD100 expression in the endothelium as well as in in vitro cultured endothelial cells. Blocking of CD 100, plexin B1 and/or B2 in adhesion experiments have shown that both CD100 and plexins act as adhesion molecules involved in monocyte-endothelial cell binding. This effect may be mediated by CD100 expressed in both cell types, probably coupled to the receptors endothelial plexin B1 and monocytic plexin B2. These results can bring new insights about a possible biological activity of CD100 in monocyte adhesion and atherosclerosis, as well as a future candidate for targeting therapeutics. (C) 2015 The Authors.
- Protein Disulfide Isomerase-A1 (PDIA1) Governs the Morphology of Endoplasmic Reticulum-Plasma Membrane Contact Sites(2022) BESSA, Tiphany De; OLIVEIRA, Percillia; WOSNIAK JR., Joao; DEBBAS, Victor; SANTOS, Celio; SHAH, Ajay; LAURINDO, Francisco R.
- Endoplasmic reticulum - plasma membrane contact sites as a potential hub for Protein Disulfide Isomerase-A1 (PDIA1) / NADPH oxidase cross-talk(2023) BESSA, Tiphany De; OLIVEIRA, Percillia; DEBBAS, Victor; WOSNIAK JR., Joao; SANTOS, Celio; SHAH, Ajay; LAURINDO, Francisco R.
- Mechanisms underlying hypertriglyceridemia in rats with monosodium L-glutamate-induced obesity: Evidence of XBP-1/PDI/MTP axis activation(2014) FRANCA, Lucas Martins; FREITAS, Larissa Nara Costa; CHAGAS, Vinicyus Teles; COELHO, Caio Fernando Ferreira; BARROSO, Wermerson Assuncao; COSTA, Graciomar Conceicao; SILVA, Lucilene Amorim; DEBBAS, Victor; LAURINDO, Francisco Rafael Martins; PAES, Antonio Marcus de AndradeNon-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium L-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression.