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
15 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 15
conferenceObject Peri/epicellular protein disulfide isomerase PDI acts as an organizer of cytoskeletal mechanoadaptation in vascular smooth muscle cells(2018) TANAKA, Leonardo Yuji; ARAUJO, Thais Larissa; RODRIGUEZ, Andres Ignacio; FERRAZ, Mariana Sacrini Ayres; PELEGATI, Vitor Bianchin; SANTOS, Aline Mara; CESAR, Carlos Lens; ALENCAR, Adriano Mesquita; LAURINDO, Francisco Rafael Martins- 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.
- 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.
- Endothelium-Dependent Vasodilation: Nitric Oxide and Other Mediators(2018) LAURINDO, F. R. M.; LIBERMAN, M.; FERNANDES, D. C.; LEITE, P. F.Vasodilation is the archetypal function of the endothelial cell and the discovery of paracrine-dependent vasorelaxation by endothelium-derived production of the gaseous mediator nitric oxide (NO) was revolutionary. NO mediates its regulatory vasorelaxing effects through guanilyl cyclase activation. Also, thiol S-nitrosation by NO is increasingly evident as an effector mechanism. Another important NO-related chemistry is its reaction with superoxide radicals, yielding peroxynitrite and related oxidant and nitrating species associated with toxic effects. Nitrogen oxides are storage forms of NO which can exert vasodilation in the presence of hemeproteins. NO generation is mediated by NO synthase enzymes (endothelial, neuronal, and inducible isoforms), which depict complex regulation dependent on cofactors. The absence of such cofactors can uncouple NO generation from electron transfer, generating superoxide. The endothelium additional promotes vasodilation, mainly of small resistance arteries, through endothelium-derived hyperpolarizing factor(s) such as hydrogen peroxide, epoximetabolites of arachidonic acid, and gap junctions. Hydrogen sulfide is a novel gaseous endothelium-derived vasodilator. Together, these mechanisms compose an integrative platform providing an endothelium-associated dilator tone. © 2018 Elsevier Inc. All rights reserved.
- Leflunomide counter(akt)under-bars cardiac hypertrophy(2018) PESCATORE, Luciana A.; LAURINDO, Francisco R. M.Cardiac hypertrophy (CH) is a major independent risk factor for heart failure and mortality. However, therapeutic interventions that target hypertrophy signaling in a load-independent way are unavailable. In a recent issue of Clinical Science (vol. 132, issue 6, 685-699), Ma et al. describe that the anti-inflammatory drug leflunomide markedly antagonized CH, dysfunction, and fibrosis induced by aortic banding or angiotensin-II in mice or by agonists in cultured cells. Unexpectedly, this occurred not via anti-inflammatory mechanisms but rather via inhibtion of Akt (protein kinase B, PKB) signaling. We further discuss the mechanisms underlying Akt activation and its effects on CH and review possible mechanisms of leflunomide effects. Despite some caveats, the availability of such a newly repurposed compound to treat CH can be a relevant advance.
- Implications of plasma thiol redox in disease(2018) OLIVEIRA, Percillia V. S.; LAURINDO, Francisco R. M.Thiol groups are crucially involved in signaling/homeostasis through oxidation, reduction, and disulphide exchange. The overall thiol pool is the resultant of several individual pools of small compounds (e.g. cysteine), peptides (e.g. glutathione), and thiol proteins (e.g. thioredoxin (Trx)), which are not in equilibrium and present specific oxidized/reduced ratios. This review addresses mechanisms and implications of circulating plasma thiol/disulphide redox pools, which are involved in several physiologic processes and explored as disease biomarkers. Thiol pools are regulated by mechanisms linked to their intrinsic reactivity against oxidants, concentration of antioxidants, thiol-disulphide exchange rates, and their dynamic release/removal from plasma. Major thiol couples determining plasma redox potential (Eh) are reduced cysteine (CyS)/cystine (the disulphide form of cysteine) (CySS), followed by GSH/disulphide-oxidized glutathione (GSSG). Hydrogen peroxide and hypohalous acids are the main plasma oxidants, while water-soluble and lipid-soluble small molecules are the main antioxidants. The thiol proteome and thiol-oxidoreductases are emerging investigative areas given their specific disease-related responses (e.g. protein disulphide isomerases (PDIs) in thrombosis). Plasma cysteine and glutathione redox couples exhibit pro-oxidant changes directly correlated with ageing/age-related diseases. We further discuss changes in thiol-disulphide redox state in specific groups of diseases: cardiovascular, cancer, and neurodegenerative. These results indicate association with the disease states, although not yet clear-cut to yield specific biomarkers. We also highlight mechanisms whereby thiol pools affect atherosclerosis pathophysiology. Overall, it is unlikely that a single measurement provides global assessment of plasma oxidative stress. Rather, assessment of individual thiol pools and thiol-proteins specific to any given condition has more solid and logical perspective to yield novel relevant information on disease risk and prognosis.
- Endothelium in Atherosclerosis: Plaque Formation and Its Complications(2018) LUZ, P. L. da; CHAGAS, A. C. P.; DOURADO, P. M. M.; LAURINDO, F. R. M.Atherosclerosis refers to the slow process of plaque formation on the walls of the arteries and includes the deposit of fat and cellular debris in the inner wall of the arteries, inflammation, proliferative responses and apoptosis. Arteries become progressively thickened and often calcified. Typically, the atherosclerotic process begins in the first decades of life and progresses slowly. Aging and genetic susceptibility play a preponderant role in the evolution of atherosclerosis. The pathophysiological understanding of atherosclerosis has gone through several stages. Today, it is understood as an inflammatory/proliferative disease. Endothelial dysfunction plays a central role in the formation of atherosclerotic plaque, in its progression, and in complications. Therefore, the main objective of this chapter is to offer an integrated review of the main factors that participate in the formation of the atherosclerotic plaque with specific focus on the endothelium. © 2018 Elsevier Inc. All rights reserved.
- Influence of apocynin on cardiac remodeling in rats with streptozotocin-induced diabetes mellitus(2018) GIMENES, R.; GIMENES, C.; ROSA, C. M.; XAVIER, N. P.; CAMPOS, D. H. S.; FERNANDES, A. A. H.; CEZAR, M. D. M.; GUIRADO, G. N.; PAGAN, L. U.; CHAER, I. D.; FERNANDES, D. C.; LAURINDO, F. R.; CICOGNA, A. C.; OKOSHI, M. P.; OKOSHI, K.Background: Increased reactive oxygen species (ROS) generation in diabetes mellitus (DM) is an important mechanism leading to diabetic cardiomyopathy. Apocynin, a drug isolated from the herb Picrorhiza kurroa, is considered an antioxidant agent by inhibiting NADPH oxidase activity and improving ROS scavenging. This study analyzed the influence of apocynin on cardiac remodeling in diabetic rats. Methods: Six-month-old male Wistar rats were assigned into 4 groups: control (CTL, n = 15), control + apocynin (CTL + APO, n = 20), diabetes (DM, n = 20), and diabetes + apocynin (DM + APO, n = 20). DM was induced by streptozotocin. Seven days later, apocynin (16 mg/kg/day) or vehicle was initiated and maintained for 8 weeks. Left ventricular (LV) histological sections were used to analyze interstitial collagen fraction. NADPH oxidase activity was evaluated in LV samples. Comparisons between groups were performed by ANOVA for a 2 x 2 factorial design followed by the Bonferroni post hoc test. Results: Body weight (BW) was lower and glycemia higher in diabetic animals. Echocardiogram showed increased left atrial diameter, LV diastolic diameter, and LV mass indexed by BW in both diabetic groups; apocynin did not affect these indices. LV systolic function was impaired in DM groups and unchanged by apocynin. Isovolumic relaxation time was increased in DM groups; transmitral E/A ratio was higher in DM + APO compared to DM. Myocardial functional evaluation through papillary muscle preparations showed impaired contractile and relaxation function in both DM groups at baseline conditions. After positive inotropic stimulation, developed tension (DT) was lower in DM than CTL. In DM + APO, DT had values between those in DM and CTL + APO and did not significantly differ from either group. Myocardial interstitial collagen fraction was higher in DM than CTL and did not differ between DM + APO and CTL + APO. Serum activity of antioxidant enzymes glutathione peroxidase, superoxide dismutase (SOD), and catalase was lower in DM than CTL; apocynin restored catalase and SOD levels in DM + APO. Myocardial NADPH oxidase activity did not differ between groups. Conclusion: Apocynin restores serum antioxidant enzyme activity despite unchanged myocardial NADPH oxidase activity in diabetic rats.
- Cardioprotective Effects of Melatonin in Reperfusion Injury(2018) LAURINDO, Francisco R. M.
- Internacionalizar é Preciso, mas é o Bastante?(2018) OLIVEIRA, Glaucia Maria Moraes de; LORENZO, Andrea De; COLOMBO, Fernanda Marciano Consolim; STERNICK, Eduardo Back; BRANDAO, Andrea Araujo; KAISER, Sergio Emanuel; QUADROS, Alexandre Schaan de; KALIL, Renato Abdala Karam; SCARAMELLO, Christianne Bretas Vieira; LAURINDO, Francisco Rafael Martins; HAJJAR, Ludhmila Abrahao