FRANCISCO RAFAEL MARTINS LAURINDO
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/64, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/64, Hospital das Clínicas, Faculdade de Medicina - Líder
24 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 24
- Time-Dependent Effects of Training on Cardiovascular Control in Spontaneously Hypertensive Rats: Role for Brain Oxidative Stress and Inflammation and Baroreflex Sensitivity(2014) MASSON, Gustavo S.; COSTA, Tassia S. R.; YSHII, Lidia; FERNANDES, Denise C.; SOARES, Pedro Paulo Silva; LAURINDO, Francisco R.; SCAVONE, Cristoforo; MICHELINI, Lisete C.Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-kappa B content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172 +/- 3 mmHg), pressure variability and heart rate (358 +/- 7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47(phox) and reactive oxygen species production, elevated NF-kappa B activity and increased TNF-alpha and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04 +/- 0.31 vs. 2.31 +/- 0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (-13%) at the 4th week, and, by reduced vasomotor component of pressure variability (-28%) and decreased mean arterial pressure (-7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.
conferenceObject Reflex modulation of vasomotor sympathetic and peripheral autonomic control on hypertension: Sequential effects of aerobic training(2020) MASSON, Gustavo Santos; FERNANDES, Denise; YSHII, Lidia; SOARES, Pedro Paulo; LAURINDO, Francisco R.; SCAVONE, Cristoforo; MICHELINIL, Lisete C.- 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.
conferenceObject GUT MICROBIOTA DIFFERS IN PHYSICALLY ACTIVE AND INACTIVE PATIENTS WITH STABLE CORONARY HEART DISEASE(2022) HAAS, Elisa; SANTOS, Andrey; LEMOS JUNIOR, Wilson J.; TREU, Laura; LAURINDO, Francisco R.; LUZ, Protasio Lemos Da- N-glycans as a tool to monitor subcellular Protein Disulfide Isomerase traffic(2023) OLIVEIRA, Percillia; TORRE, Marco Dalla; ORSI, Andrea; LAURINDO, Francisco R.; SITIA, Roberto
- 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.
- Testosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src-Dependent Pathways(2012) CHIGNALIA, Andreia Z.; SCHULDT, Elke Z.; CAMARGO, Livia L.; MONTEZANO, Augusto C.; CALLERA, Glaucia E.; LAURINDO, Francisco R.; LOPES, Lucia R.; AVELLAR, Maria Christina W.; CARVALHO, Maria Helena C.; FORTES, Zuleica B.; TOUYZ, Rhian M.; TOSTES, Rita C.Testosterone has been implicated in vascular remodeling associated with hypertension. Molecular mechanisms underlying this are elusive, but oxidative stress may be important. We hypothesized that testosterone stimulates generation of reactive oxygen species (ROS) and migration of vascular smooth muscle cells (VSMCs), with enhanced effects in cells from spontaneously hypertensive rats (SHRs). The mechanisms (genomic and nongenomic) whereby testosterone induces ROS generation and the role of c-Src, a regulator of redox-sensitive migration, were determined. VSMCs from male Wistar-Kyoto rats and SHRs were stimulated with testosterone (10(-7) mol/L, 0-120 minutes). Testosterone increased ROS generation, assessed by dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence (30 minutes [SHR] and 60 minutes [both strains]). Flutamide (androgen receptor antagonist) and actinomycin D (gene transcription inhibitor) diminished ROS production (60 minutes). Testosterone increased Nox1 and Nox4 mRNA levels and p47phox protein expression, determined by real-time PCR and immunoblotting, respectively. Flutamide, actinomycin D, and cycloheximide (protein synthesis inhibitor) diminished testosterone effects on p47phox. c-Src phosphorylation was observed at 30 minutes (SHR) and 120 minutes (Wistar-Kyoto rat). Testosterone-induced ROS generation was repressed by 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine (c-Src inhibitor) in SHRs and reduced by apocynin (antioxidant/NADPH oxidase inhibitor) in both strains. Testosterone stimulated VSMCs migration, assessed by the wound healing technique, with greater effects in SHRs. Flutamide, apocynin, and 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day] pyrimidin-4-amine blocked testosterone-induced VSMCs migration in both strains. Our study demonstrates that testosterone induces VSMCs migration via NADPH oxidase-derived ROS and c-Src-dependent pathways by genomic and nongenomic mechanisms, which are differentially regulated in VSMCs from Wistar-Kyoto rats and SHRs.
- 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.
- Protein Disulfide Isomerase overexpression induces mitochondrial reorganization and a differentiated VSMC phenotype: role of mitofusin-2(2023) WOSNIAK JR., Joao; RODRIGUES, Rafael F. G.; KAKIMOTO, Pamela A.; SILVA, Camille C. Caldeira da; ANTUNES, Fernanda; STRAUSS, Bryan E.; KOWALTOWSKI, Alicia; LAURINDO, Francisco R.
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